Journal articles on the topic 'Hyperalgesia'
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1
Alvarez, Pedro, Xiaojie Chen, Oliver Bogen, Paul G. Green, and Jon D. Levine. "IB4(+) nociceptors mediate persistent muscle pain induced by GDNF." Journal of Neurophysiology 108, no. 9 (November 1, 2012): 2545–53. http://dx.doi.org/10.1152/jn.00576.2012.
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Skeletal muscle is a well-known source of glial cell line-derived neurotrophic factor (GDNF), which can produce mechanical hyperalgesia. Since some neuromuscular diseases are associated with both increased release of GDNF and intense muscle pain, we explored the role of GDNF as an endogenous mediator in muscle pain. Intramuscularly injected GDNF induced a dose-dependent (0.1–10 ng/20 μl) persistent (up to 3 wk) mechanical hyperalgesia in the rat. Once hyperalgesia subsided, injection of prostaglandin E2 at the site induced a prolonged mechanical hyperalgesia (>72 h) compared with naïve rats (<4 h; hyperalgesic priming). Selective neurotoxic destruction of IB4(+) nociceptors attenuated both GDNF hyperalgesia and hyperalgesic priming. Ergonomic muscular injury induced by eccentric exercise or mechanical vibration increased muscle GDNF levels at 24 h, a time point where rats also exhibited marked muscle hyperalgesia. Intrathecal antisense oligodeoxynucleotides to mRNA encoding GFRα1, the canonical binding receptor for GDNF, reversibly inhibited eccentric exercise- and mechanical vibration-induced muscle hyperalgesia. Finally, electrophysiological recordings from nociceptors innervating the gastrocnemius muscle in anesthetized rats, revealed significant increase in response to sustained mechanical stimulation after local GDNF injection. In conclusion, these data indicate that GDNF plays a role as an endogenous mediator in acute and induction of chronic muscle pain, an effect likely to be produced by GDNF action at GFRα1 receptors located in IB4(+) nociceptors.
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Klamt, Jyrson G. "Effects of Intrathecally Administered Lamotrigine, a Glutamate Release Inhibitor, on Short- and Long-term Models of Hyperalgesia in Rats." Anesthesiology 88, no. 2 (February 1, 1998): 487–94. http://dx.doi.org/10.1097/00000542-199802000-00028.
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Background Lamotrigine is a sodium channel blocker that inhibits the neuronal release of glutamate. Systemic administration of lamotrigine induces analgesia in short- and long-term models of hyperalgesia in rats. Considering the key role of N-methyl-D-aspartate receptors in the sensitization of dorsal horn neurons that leads to hyperalgesia, the author hypothesizes that intrathecally injected lamotrigine would be effective in reducing the hyperalgesia. Methods Short-term hyperalgesia was induced by unilateral intraplantar injection of prostaglandin E2. Long-term hyperalgesia was produced by treating rats with streptozotocin, which causes diabetic neuropathy and, in a different group of animals, by loose ligation of the sciatic nerve (chronic constriction injury). Hyperalgesia was assessed by measuring withdrawal reaction time after paw pressure, and analgesia was measured by the thermal tail-flick test. Results In the short-term model, intrathecally administered lamotrigine (12.5, 25.0, and 100.0 microg) produced a dose-dependent increase in the reaction time of the hyperalgesic paw. The highest dose that completely restored the reaction time to control levels (26-29 s) from the hyperalgesic levels (12-15 s) did not affect the reaction time of the normal contralateral paw. In the tail-flick test, a consistent effect could be observed only with doses of 200 microg, which caused transient motor impairment of the hind paws. In the long-term models of hyperalgesia, intrathecally administered lamotrigine produced a dose-dependent and long-lasting (24-48 h) antihyperalgesic effect. Conclusions Intrathecally administered lamotrigine produced a spinal, dose-dependent, and long-lasting antihyperalgesic effect in short- and long-term neuropathic models of hyperalgesia.
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Hans, Guy H., Everhard Vandervliet, Kristof Deseure, and Paul M. Parizel. "Cerebral Activation during Von Frey Filament Stimulation in Subjects with Endothelin-1-Induced Mechanical Hyperalgesia: A Functional MRI Study." BioMed Research International 2013 (2013): 1–11. http://dx.doi.org/10.1155/2013/610727.
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Endothelin-1 (ET-1) is an endogenously expressed potent peptide vasoconstrictor. There is growing evidence that ET-1 plays a role in the pain signaling system and triggers overt nociception in humans. The underlying neuronal pathways are still a matter of great debate. In the present study, we applied an intradermal ET-1 sensitization model to induce mechanical hyperalgesia in healthy subjects. Functional magnetic resonance imaging (fMRI) was used to tease out the cortical regions associated with the processing of ET-1-induced punctate hyperalgesia, as compared to a nonnoxious mechanical stimulation of the contralateral arm. Von Frey hair testing revealed the presence of increased responsiveness to punctate stimulation in all subjects. Activational patterns between nonpainful control stimulation and hyperalgesic stimulation were compared. Two major observations were made: (1) all cortical areas that showed activation during the control stimulation were also present during hyperalgesic stimulation, but in addition, some areas showed bilateral activation only during hyperalgesic stimulation, and (2) some brain areas showed significantly higher signal changes during hyperalgesic stimulation. Our findings suggest that injection of ET-1 leads to a state of punctate hyperalgesia, which in turn causes the activation of multiple brain regions. This indicates that ET-1 activates an extended neuronal pathway.
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Roman, K., M. Yang, and Robert L. Stephens. "Characterization of the Visceral Antinociceptive Effect of Glial Glutamate Transporter GLT-1 Upregulation by Ceftriaxone." ISRN Pain 2013 (December 25, 2013): 1–10. http://dx.doi.org/10.1155/2013/726891.
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Recent studies demonstrate that glial glutamate transporter-1 (GLT-1) upregulation attenuates visceral nociception. The present work further characterized the effect of ceftriaxone- (CTX-) mediated GLT-1 upregulation on visceral hyperalgesia. Intrathecal pretreatment with dihydrokainate, a selective GLT-1 antagonist, produced a reversal of the antinociceptive response to bladder distension produced by CTX. The hyperalgesic response to urinary bladder distension caused by intravesicular acrolein was also attenuated by CTX treatment as was the enhanced time spent licking of abdominal area due to intravesicular acrolein. Bladder inflammation via cyclophosphamide injections enhanced the nociceptive to bladder distension; cohorts administered CTX and concomitant cyclophosphamide showed reduced hyperalgesic response. Cyclophosphamide-induced bladder hyperalgesia correlated with a significant 22% increase in GluR1 AMPA receptor subunit expression in the membrane fraction of the lumbosacral spinal cord, which was attenuated by CTX coadministration. Finally, neonatal colon insult-induced hyperalgesia caused by intracolonic mustard oil (2%) administration at P9 and P11 was attenuated by CTX. These studies suggest that GLT-1 upregulation (1) attenuates the hyperalgesia caused by bladder irritation/inflammation or by neonatal colonic insult, (2) acts at a spinal site, and (3) may produce antinociceptive effects by attenuating GluR1 membrane trafficking. These findings support further consideration of this FDA-approved drug to treat chronic pelvic pain syndromes.
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Masue, Tatsuhiko, Shuji Dohi, Toshio Asano, and Hiroyuki Shimonaka. "Spinal Antinociceptive Effect of Epidural Nonsteroidal Antiinflammatory Drugs on Nitric Oxide-induced Hyperalgesia in Rats." Anesthesiology 91, no. 1 (July 1, 1999): 198–206. http://dx.doi.org/10.1097/00000542-199907000-00028.
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Background Nonsteroidal antiinflammatory drugs (NSAIDs) suppress various hyperalgesia perhaps via inhibition of cyclooxygenase activity at the spinal cord. The present study aimed to examine whether epidural application of NSAIDs affects hyperalgesia induced by nitric oxide. Methods The authors studied the antinociceptive effects of epidurally administered NSAIDs in rats with a chronically in-dwelling epidural catheter by three hyperalgesic models, including nitric oxide-induced hyperalgesia by nitroglycerin (10 microg) or l-arginine (100 microg), and the biphasic response in the formalin test. Results Epidural, but not systemic, nitroglycerin induced hyperalgesia that was completely blocked by methylene blue but not by N(omega)-nitro-L-arginine methyl ester (L-NAME). Epidural l-arginine, but not d-arginine, also induced hyperalgesia that was completely blocked by L-NAME. Epidural S(+)ibuprofen (100-1,000 microg) suppressed the nitroglycerin- and l-arginine-induced thermal hyperalgesia and also the second phase response in the formalin test. Neither systemic S(+)ibuprofen nor epidural R(-)ibuprofen suppressed the hyperalgesia Epidural indomethacin (10-100 microg) or diclofenac (10-1,000 microg) dose-dependently suppressed nitroglycerin-induced thermal hyperalgesia The order of potency for this suppression (ID50 in microg) was indomethacin = didofenac > S(+)ibuprofen > R(-)ibuprofen. Conclusions The antinociceptive action of epidurally administered NSAIDs could be the result of suppression of spinal sensitization, perhaps induced with nitric oxide in the spinal cord. The ID50 values for epidural indomethacin, diclofenac, and S(+)ibuprofen were about 10 times higher than those reported in other studies for intrathecal NSAIDs in hyperalgesia models. (Key words: Cyclooxygenase inhibitors; NO donor; NO precursor; optical isomers; neuroplasticity.)
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Khasar, Sachia G., Gordon McCarter, and Jon D. Levine. "Epinephrine Produces a β-Adrenergic Receptor-Mediated Mechanical Hyperalgesia and In Vitro Sensitization of Rat Nociceptors." Journal of Neurophysiology 81, no. 3 (March 1, 1999): 1104–12. http://dx.doi.org/10.1152/jn.1999.81.3.1104.
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Epinephrine produces a β-adrenergic receptor-mediated mechanical hyperalgesia and in vitro sensitization of nociceptor-like neurons in the rat. Hyperalgesic and nociceptor sensitizing effects mediated by the β-adrenergic receptor were evaluated in the rat. Intradermal injection of epinephrine, the major endogenous ligand for the β-adrenergic receptor, into the dorsum of the hindpaw of the rat produced a dose-dependent mechanical hyperalgesia, quantified by the Randall-Selitto paw-withdrawal test. Epinephrine-induced hyperalgesia was attenuated significantly by intradermal pretreatment with propranolol, a β-adrenergic receptor antagonist, but not by phentolamine, an α-adrenergic receptor antagonist. Epinephrine-induced hyperalgesia developed rapidly; it was statistically significant by 2 min after injection, reached a maximum effect within 5 min, and lasted 2 h. Injection of a more β-adrenergic receptor-selective agonist, isoproterenol, also produced dose-dependent hyperalgesia, which was attenuated by propranolol but not phentolamine. Epinephrine-induced hyperalgesia was not affected by indomethacin, an inhibitor of cyclo-oxygenase, or by surgical sympathectomy. It was attenuated significantly by inhibitors of the adenosine 3′,5′-cyclic monophosphate signaling pathway (the adenylyl cyclase inhibitor, SQ 22536, and the protein kinase A inhibitors, Rp-adenosine 3′,5′-cyclic monophosphate and WIPTIDE), inhibitors of the protein kinase C signaling pathway (chelerythrine and bisindolylmaleimide) and a μ-opioid receptor agonist DAMGO ([d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin). Consistent with the hypothesis that epinephrine produces hyperalgesia by a direct action on primary afferent nociceptors, it was found to sensitize small-diameter dorsal root ganglion neurons in culture, i.e., to produce an increase in number of spikes and a decrease in latency to firing during a ramped depolarizing stimulus. These effects were blocked by propranolol. Furthermore epinephrine, like several other direct-acting hyperalgesic agents, caused a potentiation of tetrodotoxin-resistant sodium current, an effect that was abolished by Rp-adenosine 3′,5′-cyclic monophosphate and significantly attenuated by bisindolylmaleimide. Isoproterenol also potentiated tetrodotoxin-resistant sodium current. In conclusion, epinephrine produces cutaneous mechanical hyperalgesia and sensitizes cultured dorsal root ganglion neurons in the absence of nerve injury via an action at a β-adrenergic receptor. These effects of epinephrine are mediated by both the protein kinase A and protein kinase C second-messenger pathways.
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Koppert, Wolfgang, Reinhard Sittl, Karin Scheuber, Monika Alsheimer, Martin Schmelz, and Jürgen Schüttler. "Differential Modulation of Remifentanil-induced Analgesia and Postinfusion Hyperalgesia by S -Ketamine and Clonidine in Humans." Anesthesiology 99, no. 1 (July 1, 2003): 152–59. http://dx.doi.org/10.1097/00000542-200307000-00025.
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Background Experimental studies and clinical observations suggest a possible role for opioids to induce pain and hyperalgesia on withdrawal. The authors used a new experimental pain model in human skin to determine the time course of analgesic and hyperalgesic effects of the mu-receptor agonist remifentanil alone or in combination with the N-methyl-D-aspartate-receptor antagonist S-ketamine or the alpha(2)-receptor agonist clonidine. Methods Thirteen volunteers were enrolled in this randomized, double-blind, placebo-controlled study. Transcutaneous electrical stimulation at a high current density (2 Hz, 67.3 +/- 16.8 mA, mean +/- SD) induced acute pain (numerical 11-point rating scale: 5-6 out of 10) and stable areas of mechanical hyperalgesia to punctate stimuli and touch (allodynia). The magnitude of pain and area of hyperalgesia were assessed before, during, and after drug infusion (remifentanil at 0.1 microg x kg-1 x min-1 and S-ketamine at 5 microg x kg-1 x min-1 over a period of 30 min, respectively; clonidine infusion at 2 microg/kg for 5 min). Results Remifentanil reduced pain and areas of punctate hyperalgesia during infusion. In contrast, postinfusion pain and hyperalgesia were significantly higher than control. During infusion of S-ketamine, pain and hyperalgesia decreased and gradually normalized after infusion. When given in combination, S-ketamine abolished postinfusion increase of punctate hyperalgesia but did not reduce increased pain ratings. Clonidine alone did not significantly attenuate pain or areas of hyperalgesia. However, when given in combination with remifentanil, clonidine attenuated postinfusion increase of pain ratings. Conclusions Opioid-induced postinfusion hyperalgesia could be abolished by S-ketamine, suggesting an N-methyl-d-aspartate-receptor mechanism. In contrast, elevated pain ratings after infusion were not reduced by ketamine but were alleviated by the alpha(2)-receptor agonist clonidine. The results of this study suggest different mechanisms of opioid-induced postinfusion antianalgesia and secondary hyperalgesia.
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Aghade, Karveer Babanrao. "Effect of caffeine on capsaicin induced hyperalgesia in mice." Indian Journal of Pharmacy and Pharmacology 10, no. 3 (October 15, 2023): 197–203. http://dx.doi.org/10.18231/j.ijpp.2023.037.
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Caffeine is the most widely consumed behaviorally active substance in the world. In the past several pharmaceutical companies used caffeine along with other drugs to get analgesic effect. The present research work was undertaken to investigate the effect of interaction of caffeine and capsaicin on animal model of hyperalgesia in mice. To meet these objectives, effect of drugs was studied using tail immersion test, an animal model of thermal hyperalgesia and tail withdrawal test in mice, an animal model of cold hyperalgesia. The efficacy of three active principles alone and in combination of indomethacin, caffeine and prochlorperazine in reverting hyperalgesia was studied. Indomethacin 0.3 mg/ kg, i.p., caffeine 0.1 & 0.3 mg/ kg, i.p. and prochlorperazine 0.1 mg/ kg as well as combination reverted morphine withdrawal induced hyperalgesia. Initial application of capsaicin was found to be algesic leading to noxious stimulation in peripheral nervous system, which may cause allodynia and hyperalgesia. Thus this mechanism is also being studied in this study. Since most of the centrally acting analgesics act by way of their effect on dopaminergic mechanism and modifying calcium release, further studies on hyperalgesic activity were carried out using caffeine, capsaicin, amlodipine, haloperidol in the tail immersion (hot water of 55°C) and the tail withdrawal test (cold ethanol -14°C).
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Hughes, Sam W., Meirvaan Basra, Calvin Chan, Callum Parr, Felyx Wong, Sofia Gomes, and Paul H. Strutton. "Capsaicin-Induced Changes in Electrical Pain Perception Threshold Can Be Used to Assess the Magnitude of Secondary Hyperalgesia in Humans." Pain Medicine 21, no. 11 (April 26, 2020): 2830–38. http://dx.doi.org/10.1093/pm/pnaa082.
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Abstract Objectives Areas of secondary hyperalgesia can be assessed using quantitative sensory testing (QST). Delivering noxious electrocutaneous stimulation could provide added benefit by allowing multiple measurements of the magnitude of hyperalgesia. We aimed to characterize the use of electrical pain perception (EPP) thresholds alongside QST as a means by which to measure changes in pain thresholds within an area of secondary mechanical hyperalgesia. Methods EPP and heat pain thresholds (HPTs) were measured at five distinct points at baseline and following 1% capsaicin cream application, one within a central zone and four within a secondary zone. Areas of secondary mechanical hyperalgesia were mapped using QST. In a further 14 participants, capsaicin-induced reduction in EPP thresholds was mapped using a radial lines approach across 24 points. Results There was a reduction in EPP threshold measured at the four points within the secondary zone, which was within the mapped area of mechanical secondary hyperalgesia. The magnitude of secondary hyperalgesia could be split into a mild (∼4% reduction) and severe (∼21% reduction) area within an individual subject. There was no reduction in HPT within the secondary zone, but there was a reduction in both HPT and EPP threshold within the primary zone. EPP mapping revealed differences in the magnitude and spread of hyperalgesia across all subjects. Conclusions Measuring capsaicin-induced reduction in EPP thresholds can be used to map hyperalgesic areas in humans. This semi-automated approach allows rapid assessment of the magnitude of hyperalgesia, both within an individual subject and across a study population.
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Holtman, Joseph R., and Elzbieta P. Wala. "Characterization of the Antinociceptive and Pronociceptive Effects of Methadone in Rats." Anesthesiology 106, no. 3 (March 1, 2007): 563–71. http://dx.doi.org/10.1097/00000542-200703000-00022.
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Background Recently, it has been appreciated that in addition to their antinociceptive properties, opioid analgesics also can enhance pain sensitivity (opioid-induced hyperalgesia [OIH]). OIH may enhance preexisting pain and contribute to dose escalation, tolerance, and misuse/abuse of opioids. Better information is needed to determine which opioid or opioid combinations may be least likely to produce OIH and therefore possibly represent better choices for pain management. Herein the authors have examined the hyperalgesic and antinociceptive properties of racemic methadone and its enantiomers alone and in combination with morphine in rats. Methadone is of particular interest because it possesses both micro-receptor agonist and N-methyl-d-aspartate receptor antagonist activities. Methods The antinociceptive and hyperalgesic properties of d,l-methadone, l-methadone, and d-methadone were characterized by dose and sex using the thermal tail-flick test (high and low intensity). The responses to l- and d-methadone combinations with morphine were also determined with this model. Results Antinociceptive and hyperalgesic effects of d,l-methadone were demonstrated. These effects were related to dose but not to sex. The degree of hyperalgesia was greater with l-methadone compared with d,l-methadone. In contrast, d-methadone (N-methyl-d-aspartate antagonist) did not produce hyperalgesia. Furthermore, d-methadone blocked morphine hyperalgesia, enhanced antinociception, and abolished sex-related differences. This seems to be the result of antagonistic activity of d-methadone at the N-methyl-d-aspartate receptor. Conclusion The current findings with methadone are supportive of previous findings implicating mu-opioid and N-methyl-d-aspartate receptor mechanisms in OIH. Better understanding of OIH may help in choosing the most appropriate opioids for use in the treatment of pain.
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Tsuchida, Keiichiro, Takae Ibuki, and Kiyoshi Matsumura. "Bromoenol Lactone, an Inhibitor of Calcium-Independent Phospholipase A2, Suppresses Carrageenan-Induced Prostaglandin Production and Hyperalgesia in Rat Hind Paw." Mediators of Inflammation 2015 (2015): 1–7. http://dx.doi.org/10.1155/2015/605727.
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Prostaglandin (PG) E2and PGI2are essential to hyperalgesia in inflammatory tissues. These prostaglandins are produced from arachidonic acid, which is cleaved from membrane phospholipids by the action of phospholipase A2(PLA2). Which isozyme of PLA2is responsible for the cleavage of arachidonic acid and the production of prostaglandins essential to inflammation-induced hyperalgesia is not clear. In this study, we examined the effects of two PLA2isozyme-specific inhibitors on carrageenan-induced production of PGE2and PGI2in rat hind paw and behavioral nociceptive response to radiant heat. Local administration of bromoenol lactone (BEL), an inhibitor of calcium-independent PLA2(iPLA2), significantly reduced carrageenan-induced elevation of prostaglandins in the inflamed foot pad 3 h after injection. It also ameliorated the hyperalgesic response between 1 h and 3 h after carrageenan injection. On the other hand, AACOCF3, an inhibitor of cytosolic PLA2, suppressed neither prostaglandin production nor the hyperalgesic response. BEL did not suppress the mRNA levels of iPLA2β, iPLA2γ, cyclooxygenase-2, microsomal prostaglandin E synthase, prostaglandin I synthase, or proinflammatory cytokines in the inflamed foot pad, indicating that BEL did not suppress inflammation itself. These results suggest that iPLA2is involved in the production of prostaglandins and hyperalgesia at the inflammatory loci.
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Liang, M., M. C. Lee, J. O'Neill, A. H. Dickenson, and G. D. Iannetti. "Brain potentials evoked by intraepidermal electrical stimuli reflect the central sensitization of nociceptive pathways." Journal of Neurophysiology 116, no. 2 (August 1, 2016): 286–95. http://dx.doi.org/10.1152/jn.00013.2016.
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Central sensitization (CS), the increased sensitivity of the central nervous system to somatosensory inputs, accounts for secondary hyperalgesia, a typical sign of several painful clinical conditions. Brain potentials elicited by mechanical punctate stimulation using flat-tip probes can provide neural correlates of CS, but their signal-to-noise ratio is limited by poor synchronization of the afferent nociceptive input. Additionally, mechanical punctate stimulation does not activate nociceptors exclusively. In contrast, low-intensity intraepidermal electrical stimulation (IES) allows selective activation of type II Aδ-mechano-heat nociceptors (II-AMHs) and elicits reproducible brain potentials. However, it is unclear whether hyperalgesia from IES occurs and coexists with secondary mechanical punctate hyperalgesia, and whether the magnitude of the electroencephalographic (EEG) responses evoked by IES within the hyperalgesic area is increased. To address these questions, we explored the modulation of the psychophysical and EEG responses to IES by intraepidermal injection of capsaicin in healthy human subjects. We obtained three main results. First, the intensity of the sensation elicited by IES was significantly increased in participants who developed robust mechanical punctate hyperalgesia after capsaicin injection (i.e., responders), indicating that hyperalgesia from IES coexists with punctate mechanical hyperalgesia. Second, the N2 peak magnitude of the EEG responses elicited by IES was significantly increased after the intraepidermal injection of capsaicin in responders only. Third, a receiver-operator characteristics analysis showed that the N2 peak amplitude is clearly predictive of the presence of CS. These findings suggest that the EEG responses elicited by IES reflect secondary hyperalgesia and therefore represent an objective correlate of CS.
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LaMotte, R. H., C. N. Shain, D. A. Simone, and E. F. Tsai. "Neurogenic hyperalgesia: psychophysical studies of underlying mechanisms." Journal of Neurophysiology 66, no. 1 (July 1, 1991): 190–211. http://dx.doi.org/10.1152/jn.1991.66.1.190.
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1. Psychophysical studies were made, in humans, of the sensory characteristics and underlying mechanisms of the hyperalgesia (often termed “secondary hyperalgesia”) that occurs in uninjured skin surrounding a local cutaneous injury. The hyperalgesia was characterized by lowered pain thresholds and enhanced magnitude of pain to normally painful stimuli. The “injury” was produced by a single intradermal injection of 10 microliters of 100 micrograms of capsaicin, the algesic substance in hot chili peppers. 2. On injection of capsaicin into the volar forearm, the subjects experienced intense burning pain, accompanied immediately by the formation of three areas of hyperalgesia surrounding the injection site. The largest mean area (55 cm2) was hyperalgesic to a normally painful punctate stimulation of the skin. Nested within this was an area of tenderness to gentle stroking (38 cm2) and a much smaller area of hyperalgesia to heat (2 cm2). An area of analgesia to pinprick, approximately 4 mm in diameter and centered on the injection site, developed within minutes and typically disappeared within 24 h. The hyperalgesia to heat and to stroking disappeared within 1-2 h, whereas the hyperalgesia to punctate stimuli, although gradually decreasing in area, lasted from 13 to 24 h. 3. The radial spread of the mechanical hyperalgesia (to punctate and stroking stimuli) away from the injury was dependent on neural activity and not produced, for example, by algesic substances transported away from the injury. The injection of capsaicin into a small area of anesthetized skin did not produce hyperalgesia in the surrounding, unanesthetized skin. Also, the hyperalgesia in normal skin readily crossed a tight arm band that blocked the circulation of blood and lymph. 4. The spread of mechanical hyperalgesia away from the injury was peripherally mediated via cutaneous nerve fibers because it was blocked by a thin mediolateral strip of cutaneous anesthesia placed 1 cm away from the capsaicin injection site. Hyperalgesia developed normally on the capsaicin side of the strip but not on the other side. 5. Heat stimulation of the skin that produced pain that was equivalent in magnitude and time course to that produced by an injection of capsaicin (10 micrograms) resulted in much smaller areas of mechanical hyperalgesia. It was postulated that there exist special chemosensitive primary afferent nerve fibers that are more effective in producing mechanical hyperalgesia than are the known thermo- and mechanosensitive nociceptive nerve fibers. 6. Once developed, the mechanical hyperalgesia became only partially dependent on peripheral neural activity originating at the site of injury.(ABSTRACT TRUNCATED AT 400 WORDS)
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Kraft, Birgit, Nathalie A. Frickey, Rainer M. Kaufmann, Marcus Reif, Richard Frey, Burkhard Gustorff, and Hans G. Kress. "Lack of Analgesia by Oral Standardized Cannabis Extract on Acute Inflammatory Pain and Hyperalgesia in Volunteers." Anesthesiology 109, no. 1 (July 1, 2008): 101–10. http://dx.doi.org/10.1097/aln.0b013e31817881e1.
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Background Cannabinoid-induced analgesia was shown in animal studies of acute inflammatory and neuropathic pain. In humans, controlled clinical trials with Delta-tetrahydrocannabinol or other cannabinoids demonstrated analgesic efficacy in chronic pain syndromes, whereas the data in acute pain were less conclusive. Therefore, the aim of this study was to investigate the effects of oral cannabis extract in two different human models of acute inflammatory pain and hyperalgesia. Methods The authors conducted a double-blind, crossover study in 18 healthy female volunteers. Capsules containing Delta-tetrahydrocannabinol-standardized cannabis extract or active placebo were orally administered. A circular sunburn spot was induced at one upper leg. Heat and electrical pain thresholds were determined at the erythema, the area of secondary hyperalgesia, and the contralateral leg. Intradermal capsaicin-evoked pain and areas of flare and secondary hyperalgesia were measured. Primary outcome parameters were heat pain thresholds in the sunburn erythema and the capsaicin-evoked area of secondary hyperalgesia. Secondary measures were electrical pain thresholds, sunburn-induced secondary hyperalgesia, and capsaicin-induced pain. Results Cannabis extract did not affect heat pain thresholds in the sunburn model. Electrical thresholds (250 Hz) were significantly lower compared with baseline and placebo. In the capsaicin model, the area of secondary hyperalgesia, flare, and spontaneous pain were not altered. Conclusion To conclude, no analgesic or antihyperalgesic activity of cannabis extract was found in the experiments. Moreover, the results even point to the development of a hyperalgesic state under cannabinoids. Together with previous data, the current results suggest that cannabinoids are not effective analgesics for the treatment of acute nociceptive pain in humans.
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Chatterjea, Devavani, Alyssa Ashbaugh, Elena Tonc, Madison Mack, Tijana Martinov, and Akilah Sykes. "SPE-7 but not Epsilon-26 anti-dinitrophenyl-Immunoglobulin E induces antigen-dependent thermal hyperalgesia accompanying equivalent inflammatory responses during passive cutaneous anaphylaxis reactions in mice (HYP3P.405)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 54.17. http://dx.doi.org/10.4049/jimmunol.192.supp.54.17.
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Abstract Sensitization of mast cells with SPE-7 anti-DNP-IgE alone initiates inflammatory cytokine production in vitro. In contrast, ε26 anti-DNP IgE does not induce inflammatory cytokines independent of antigen-stimulation. We tested these two anti-DNP IgE clones in our model of murine thermal hyperalgesia. We found pronounced hind paw hyperalgesic responses lasting to at least 6 hours following antigen challenge 24 hours after sensitization with SPE-7 but not ε26. SPE-7/DNP did not induce greater levels of mast cell degranulation in the hind paw. Differential hyperalgesic responses were accompanied by otherwise equivalent inflammatory changes measured including histamine release, neutrophil influx, expression of TNF-α, IL-1β, and IL-6 genes and changes in levels of TNF-α, IL-1, and IL-6 proteins. Inflammatory responses and hyperalgesia were dependent on antigen challenge and were not detected in sham-challenged mice. Hyperalgesia responses or other inflammatory changes were not detected in the hind paw tissue post-sensitization in the 24 hours prior to antigen challenge. We demonstrate a novel behavioral, antigen-dependent difference between reactions mediated by these IgE antibody clones in vivo in mice. We are currently further investigating the inflammatory cytokine milieu and measuring changes in mRNA and protein levels of nociceptive signaling molecules provoked by IgE/Ag-induced cutaneous anaphylaxis to elucidate the mechanisms underlying this differential pain outcome.
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Tröster, Andreas, Ruth Sittl, Boris Singler, Martin Schmelz, Jürgen Schüttler, and Wolfgang Koppert. "Modulation of Remifentanil-induced Analgesia and Postinfusion Hyperalgesia by Parecoxib in Humans." Anesthesiology 105, no. 5 (November 1, 2006): 1016–23. http://dx.doi.org/10.1097/00000542-200611000-00024.
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Background Numerous experimental and clinical studies suggest that brief opioid exposure can enhance pain sensitivity. It is suggested that spinal cyclooxygenase activity may contribute to the development and expression of opioid tolerance. The aim of the investigation was to determine analgesic and antihyperalgesic properties of the cyclooxygenase-2 inhibitor parecoxib on remifentanil-induced hypersensitivity in humans. Methods Fifteen healthy male volunteers were enrolled in this randomized, double-blind, placebo-controlled study in a crossover design. Transcutaneous electrical stimulation at high current densities was used to induce spontaneous acute pain (numeric rating scale 6 of 10) and stable areas of pinprick hyperalgesia. Pain intensities and areas of hyperalgesia were assessed before, during, and after a 30-min intravenous infusion of remifentanil (0.1 microg x kg x min) or placebo (saline). Parecoxib (40 mg) was administered intravenously either with onset of electrical stimulation (preventive) or in parallel to the remifentanil infusion. Results Remifentanil reduced pain and mechanical hyperalgesia during the infusion, but upon withdrawal, pain and hyperalgesia increased significantly above control level. Preventive administration of parecoxib led to an amplification of remifentanil-induced antinociceptive effects during the infusion (71.3 +/- 7 vs. 46.4 +/- 17% of control) and significantly diminished the hyperalgesic response after withdrawal. In contrast, parallel administration of parecoxib did not show any modulatory effects on remifentanil-induced hyperalgesia. Conclusion The results confirm clinically relevant interaction of mu opioids and prostaglandins in humans. Adequate timing seems to be of particular importance for the antihyperalgesic effect of cyclooxygenase-2 inhibitors.
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Chen, Xiaojie, Paul G. Green, and Jon D. Levine. "Does the antihyperalgesic disruptor of endothelial cells, octoxynol-9, alter nociceptor function?" Journal of Neurophysiology 112, no. 2 (July 15, 2014): 463–66. http://dx.doi.org/10.1152/jn.00034.2014.
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The vasoactive mediator, endothelin-1, elicits a novel form of hyperalgesia, stimulation-dependent hyperalgesia. Acting on its cognate receptor on the vascular endothelial cell, endothelin-1 produces a state in which mechanical stimulation now elicits release of pronociceptive mediators from endothelium that, in turn, acts at receptors on sensory neurons. The only evidence that octoxynol-9, a surface-active agent that attenuates both endothelial cell function and stimulus-dependent hyperalgesia, does not affect nociceptors is indirect (i.e., octoxynol-9 treatment did not affect behavioral nociceptive threshold or hyperalgesia induced by agents that act directly on nociceptors). To help address the question of whether the attenuation of stimulation-dependent hyperalgesia by octoxynol-9 treatment is due to alteration of nociceptor function, we used in vivo single-fiber electrophysiological recordings. Consistent with our previous behavioral observations, we observed no significant effect of octoxynol-9 on mechanical threshold in nociceptors, their response to sustained suprathreshold mechanical stimulation, conduction velocity, and change in mechanical threshold in response to the direct-acting hyperalgesic agent, PGE2. Although octoxynol-9 did not produce a biologically meaningful change in parameters of nociceptor function, we cannot exclude the possibility of a type II error. However, our data provide preliminary evidence of no effect of octoxynol-9 on nociceptors and are consistent with the suggestion that the primary action of octoxynol-9 in our studies is due to its action on the endothelium.
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Bom, Ariela de Oliveira Pedro, Monique Dias-Soares, Raíssa Cristina Darroz Corrêa, Camila Lima Neves, Natalia Gabriele Hosch, Gabriela Gomes de Lucena, Camilla Garcia Oliveira, Rosana Lima Pagano, Marucia Chacur, and Renata Giorgi. "Molecular Aspects Involved in the Mechanisms of Bothrops jararaca Venom-Induced Hyperalgesia: Participation of NK1 Receptor and Glial Cells." Toxins 16, no. 4 (April 10, 2024): 187. http://dx.doi.org/10.3390/toxins16040187.
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Accidents caused by Bothrops jararaca (Bj) snakes result in several local and systemic manifestations, with pain being a fundamental characteristic. The inflammatory process responsible for hyperalgesia induced by Bj venom (Bjv) has been studied; however, the specific roles played by the peripheral and central nervous systems in this phenomenon remain unclear. To clarify this, we induced hyperalgesia in rats using Bjv and collected tissues from dorsal root ganglia (DRGs) and spinal cord (SC) at 2 and 4 h post-induction. Samples were labeled for Iba-1 (macrophage and microglia), GFAP (satellite cells and astrocytes), EGR1 (neurons), and NK1 receptors. Additionally, we investigated the impact of minocycline, an inhibitor of microglia, and GR82334 antagonist on Bjv-induced hyperalgesia. Our findings reveal an increase in Iba1 in DRG at 2 h and EGR1 at 4 h. In the SC, markers for microglia, astrocytes, neurons, and NK1 receptors exhibited increased expression after 2 h, with EGR1 continuing to rise at 4 h. Minocycline and GR82334 inhibited venom-induced hyperalgesia, highlighting the crucial roles of microglia and NK1 receptors in this phenomenon. Our results suggest that the hyperalgesic effects of Bjv involve the participation of microglial and astrocytic cells, in addition to the activation of NK1 receptors.
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Chung, M. K., S. Wang, J. Yang, I. Alshanqiti, F. Wei, and J. Y. Ro. "Neural Pathways of Craniofacial Muscle Pain: Implications for Novel Treatments." Journal of Dental Research 99, no. 9 (May 6, 2020): 1004–12. http://dx.doi.org/10.1177/0022034520919384.
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Craniofacial muscle pain is highly prevalent in temporomandibular disorders but is difficult to treat. Enhanced understanding of neurobiology unique to craniofacial muscle pain should lead to the development of novel mechanism-based treatments. Herein, we review recent studies to summarize neural pathways of craniofacial muscle pain. Nociceptive afferents in craniofacial muscles are predominantly peptidergic afferents enriched with TRPV1. Signals from peripheral glutamate receptors converge onto TRPV1, leading to mechanical hyperalgesia. Further studies are needed to clarify whether hyperalgesic priming in nonpeptidergic afferents or repeated acid injections also affect craniofacial muscle pain. Within trigeminal ganglia, afferents innervating craniofacial muscles interact with surrounding satellite glia, which enhances the sensitivity of the inflamed neurons as well as nearby uninjured afferents, resulting in hyperalgesia and ectopic pain originating from adjacent orofacial tissues. Craniofacial muscle afferents project to a wide area within the trigeminal nucleus complex, and central sensitization of medullary dorsal horn neurons is a critical factor in muscle hyperalgesia related to ectopic pain and emotional stress. Second-order neurons project rostrally to pathways associated with affective pain, such as parabrachial nucleus and medial thalamic nucleus, as well as sensory-discriminative pain, such as ventral posteromedial thalamic nuclei. Abnormal endogenous pain modulation can also contribute to chronic muscle pain. Descending serotonergic circuits from the rostral ventromedial medulla facilitate activation of second-order neurons in the trigeminal nucleus complex, which leads to the maintenance of mechanical hyperalgesia of inflamed masseter muscle. Patients with temporomandibular disorders exhibit altered brain networks in widespread cortical and subcortical regions. Recent development of methods for neural circuit manipulation allows silencing of specific hyperactive neural circuits. Chemogenetic silencing of TRPV1-expressing afferents or rostral ventromedial medulla neurons attenuates hyperalgesia during masseter inflammation. It is likely, therefore, that further delineation of neural circuits mediating craniofacial muscle hyperalgesia potentially enhances treatment of chronic muscle pain conditions.
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Juni, Aaron, Minying Cai, Magda Stankova, Amanda R. Waxman, Caroline Arout, Gad Klein, Albert Dahan, Victor J. Hruby, Jeffrey S. Mogil, and Benjamin Kest. "Sex-specific Mediation of Opioid-induced Hyperalgesia by the Melanocortin-1 Receptor." Anesthesiology 112, no. 1 (January 1, 2010): 181–88. http://dx.doi.org/10.1097/aln.0b013e3181c53849.
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Background N-Methyl-D-aspartate receptor antagonists reverse hyperalgesia during morphine infusion in male mice only. Because the melanocortin-1 receptor can act as a female-specific counterpart to N-methyl-D-aspartate receptors in kappa-opioid analgesic mechanisms, the authors assessed the contribution of melanocortin-1 receptors to the sex-specific mechanisms underlying morphine hyperalgesia. Methods The tail-withdrawal test was used to compare the nociceptive responses of male and female C57BL/6J (B6) mice with those of C57BL/6J-Mc(1r(e/e)) mice, spontaneous mutants of the B6 background lacking functional melanocortin-1 receptors, during continuous morphine infusion (1.6 and 40.0 mgkg(-1) . 24 h(-1)). Separate groups of hyperalgesic B6 and outbred CD-1 mice were injected with MK-801 or MSG606, selective N-methyl-D-aspartate and melanocortin-1 receptor antagonists, respectively. Results Morphine infusion (40.0 mg . kg(-1) . 24 h(-1)) reduced baseline withdrawal latencies by 45-55% in B6 mice of both sexes, indicating hyperalgesia; this increased nociception was manifest in male e/e mice only. Although MK-801 reversed hyperalgesia in male mice only, increasing latencies by 72%, MSG606 increased latencies by approximately 60% exclusively in females. A lower morphine infusion dose (1.6 mg . kg(-1) . 24 h(-1)) reduced baseline withdrawal latencies by 45-52% in B6 and e/e mice of both sexes, which was reversed by MK-801, but not MSG606, in both male and female B6 mice. Conclusions The data indicate the sex-specific mediation of high-dose morphine-induced hyperalgesia by N-methyl-d-aspartate and melanocortin-1 receptors in male and female mice, respectively, suggesting a broader relevance of this known sexual dimorphism. The data further indicate that the neural substrates contributing to hyperalgesia are morphine dose-dependent.
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Chatterjea, Devavani, Madison Mack, Abigail Wetzel, Elena Tonc, Evelyn Balsells, and Camilla Engblom. "Highly cytokinergic SPE-7 anti-dinitrophenyl-immunoglobulin E induces antigen-dependent thermal hyperalgesia and inflammatory cytokine production in the mouse hindpaw (P6000)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 59.1. http://dx.doi.org/10.4049/jimmunol.190.supp.59.1.
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Abstract SPE-7 anti-DNP-IgE initiates inflammatory cytokine production without antigen stimulation in vitro. In contrast, ϵ2624 anti-DNP IgE does not induce inflammatory cytokines independent of antigen-stimulation. However, their effects in vivo have not been described. We tested two well-characterized anti-mouse IgE antibody clones in our model of murine thermal hyperalgesia. We found pronounced hindpaw hyperalgesic responses lasting to at least 6 hours following antigen challenge after sensitization with SPE-7. These responses were accompanied by histamine release and neutrophil influx as we have previously shown in c48/80-mediated thermal hyperalgesia. In contrast, we found that antigen challenge following sensitization with clone ϵ2624 produced slight hyperalgesia at 1 hr that was resolved by 3 hours. We demonstrate a novel functional, behavioral difference between reactions mediated by these IgE antibody clones in vivo in mice. Also, SPE-7 does not lead to antigen-independent cytokine production in the mouse hind paw. After antigen challenge, both IgEs produce equivalent levels of TNF-α, IL-1, and IL-6, and cause equivalent histamine release and neutrophil influx. Thus tissue-resident sentinel mast cells may be critical initiators of allergen-evoked hyperalgesia in mice and differences in the nature and repertoire of IgE antibodies produced during an allergic response likely have pathophysiological implications for various health outcomes including pain.
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Meller, S. T. "Hyperalgesia." APS Journal 3, no. 4 (December 1994): 257–63. http://dx.doi.org/10.1016/s1058-9139(05)80273-6.
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Andresen, Trine, Dagmar Lunden, Asbjørn M. Drewes, and Lars Arendt-Nielsen. "Pain sensitivity and experimentally induced sensitisation in red haired females." Scandinavian Journal of Pain 2, no. 1 (January 1, 2011): 3–6. http://dx.doi.org/10.1016/j.sjpain.2010.08.005.
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AbstractIntroduction and aimPain sensitivity has been linked to the melanocortin-1 receptor (MC1R) gene. A mutation in MC1R can result in pale skin and red hair in humans and may modulate pain responses in general. Human studies have shown that women with non-functional MC1R’s were sensitive to experimental induced cold and heat pain. A study demonstrated that females with red hair required higher dose of anesthesia than females with dark hair to experience analgesia to electrical stimulation. Moreover, women expressing non-functional MC1Rs display greater analgesia from opioid analgesia. If redheads in general respond differently to pain and analgesics, this is of clinical importance. The aim of this study was therefore to investigate pain sensitivity and experimentally induced sensitisation in red haired females.MethodTwenty healthy females with pale skin and red hair (mean age 32 years, range 20–55) and 20 healthy females with blond/dark hair (mean age 31 years, range 20–51) participated in this study. The pain tolerance thresholds to heat and pressure stimulation were determined. Hyperalgesia was induced experimentally by applying 0.075% topical capsaicin cream for 30 min. The secondary pin-prick hyperalgesic area was estimated with a calibrated filament (von Frey hair, 15 g) and the area of allodynia by a soft brush. This was done 0, 30, 60, and 90 min after cream removal.ResultsNeither heat nor pressure pain tolerance thresholds were changed in the two groups. The secondary pin-prick hyperalgesic areas were significantly smaller for red haired females than blond/dark haired females (P = 0.014). There were no significant differences in the allodynic areas.DiscussionAs the secondary hyperalgesic response evoked by topical capsaicin is a central phenomenon, the observed smaller pin-prick hyperalgesic area in the red haired females could indicate a central role of MCRs in development or maintenance of hyperalgesia. Central involvement of MC1Rs or dysfunction of peripheral MC1Rs activating central MC4Rs has been suggested to influence pain sensitivity. The difference observed between red haired and non-red haired females may have implications for pain management regimens as compounds interacting with sensitisation such as NMDA-antagonists or alpha-2-delta-ligands may exert different types of action in people with MC1R mutation.ConclusionThe present study showed that red haired females were less sensitive to topical capsaicin induced pin-prick hyperalgesia compared with blond/dark haired females.ImplicationsThe smaller hyperalgesic area in redheads could be a manifestation of central anti-hyperalgesic involvement of MCRs and could have an influence on the treatment of pain as well as in studies investigating anti-hyperalgesic drugs.
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Bradesi, Sylvie, Vicente Martinez, Lijun Lao, Håkan Larsson, and Emeran A. Mayer. "Involvement of vasopressin 3 receptors in chronic psychological stress-induced visceral hyperalgesia in rats." American Journal of Physiology-Gastrointestinal and Liver Physiology 296, no. 2 (February 2009): G302—G309. http://dx.doi.org/10.1152/ajpgi.90557.2008.
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Visceral hypersensitivity and stress have been implicated in the pathophysiology of functional gastrointestinal disorders. We used a selective vasopressin 3 (V3) receptor antagonist SSR149415 to investigate the involvement of the vasopressin (AVP)/V3 signaling system in the development of stress-induced visceral hyperalgesia in rats. Rats were exposed to a daily 1-h session of water avoidance stress (WAS) or sham WAS for 10 consecutive days. The visceromotor response to phasic colorectal distension (CRD, 10–60 mmHg) was assessed before and after stress. Animals were treated daily with SSR149415 (0.3, 1, or 3 mg/kg ip 30 min before each WAS or sham WAS session), with a single dose of SSR149415 (1 mg/kg ip), or the selective corticotropin-releasing factor 1 (CRF1) antagonist DMP-696 (30 mg/kg po) before CRD at day 11. Effects of a single dose of SSR149415 (10 mg/kg iv) on acute mechanical sensitization during repetitive CRD (12 distensions at 80 mmHg) were also assessed. In vehicle-treated rats, repeated WAS increased the response to CRD, indicating visceral hypersensitivity. Repeated administration of SSR149415 at 1 or 3 mg/kg completely prevented stress-induced visceral hyperalgesia. Similarly, a single dose of DMP-696 or SSR149415 completely blocked hyperalgesic responses during CRD. In contrast, a single dose of SSR149415 did not affect the acute hyperalgesic responses induced by repeated, noxious distension. These data support a major role for V3 receptors in repeated psychological stress-induced visceral hyperalgesia and suggest that pharmacological manipulation of the AVP/V3 pathway might represent an attractive alternative to the CRF/CRF1 pathway for the treatment of chronic stress-related gastrointestinal disorders.
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Rondon, E. S., C. A. A. Valadão, and C. A. Parada. "Subarachnoid injection of ifenprodil and ketamine association improves the anti-hyperalgesic action of ketamine in dogs." Arquivo Brasileiro de Medicina Veterinária e Zootecnia 67, no. 6 (December 2015): 1539–46. http://dx.doi.org/10.1590/1678-4162-8057.
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To test clinically whether a small dose of ifenprodil can enhance the anti-hyperalgesic effect of ketamine in dogs, a prospective randomized cross-over study was done with eight mongrel dogs (weighing 16.9 ± 3.7kg). Animals received two distinct treatments: ketamine (0.3mg kg-1; KT) and an ifenprodil plus ketamine combination (0.03mg kg-1 and 0.3mg kg-1, respectively; IKT). Dogs were anesthetized with propofol (5mg kg-1 intravenously) and a subarachnoid needle was placed between the 5th and 6th lumbar vertebrae. Five minutes after subarachnoid injection of KT or IKT, an incision including cutaneous and subcutaneous tissues was made on the common pad of one hind limb and was immediately closed with a simple interrupted suture pattern. The dogs were treated again 20 days later, using the contralateral pad and the opposite treatment. Sedation score (SS), lameness score (LS), heart rate (HR), respiratory rate (fR), and mechanical nociceptive threshold using von Frey filaments, were evaluated before anesthesia and at 1, 1.5, 2, 3, 4, 8, 12, and 24 hours after subarachnoid injection. There were no differences in SS, LS, HR or fR between treatments. The intensity of hyperalgesia was higher in KT than in IKT for 24 hours. The anti-hyperalgesic effect of IKT remained without statistical significant difference between 1 and 24 h. Prior subarachnoid administration of ifenprodil enhances the anti-hyperalgesic effect of subarachnoid ketamine in dogs. Ifenprodil can be co-administrated with ketamine to enhance its anti-hyperalgesic effect and to reduce acute post-incisional hyperalgesia without motor impairment and sedation.
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Gustorff, Burkhard, Sibylle Kozek-Langenecker, and Hans Georg Kress. "Gabapentin: The First Preemptive Anti-Hyperalgesic for Opioid Withdrawal Hyperalgesia?" Anesthesiology 98, no. 6 (June 1, 2003): 1520–21. http://dx.doi.org/10.1097/00000542-200306000-00045.
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Gilron, Ian. "Gabapentin: The First Preemptive Anti-Hyperalgesic for Opioid Withdrawal Hyperalgesia?" Anesthesiology 98, no. 6 (June 1, 2003): 1521–22. http://dx.doi.org/10.1097/00000542-200306000-00046.
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Eisenach, James C., and G. F. Gebhart. "Intrathecal Amitriptyline Acts as an N-Methyl-D-Aspartate Receptor Antagonist in the Presence of Inflammatory Hyperalgesia in Rats." Anesthesiology 83, no. 5 (November 1, 1995): 1046–54. http://dx.doi.org/10.1097/00000542-199511000-00018.
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Abstract Background Amitriptyline and other tricyclic antidepressants exhibit high affinity binding to N-methyl-D-aspartate (NMDA) receptors in vitro and inhibit NMDA receptor activation-induced neuroplasticity in hippocampal slices. Because spinal NMDA receptor activation is believed to be central to generation and maintenance of hyperalgesic pain, the purpose of this study was to test whether intrathecal amitriptyline reduced inflammation-induced hyperalgesia in the rat.
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Tzabazis, A. Z., and W. Koppert. "Opioid-induced hyperalgesia or opioid-withdrawal hyperalgesia?" European Journal of Anaesthesiology 24, no. 9 (September 2007): 811–12. http://dx.doi.org/10.1017/s0265021507000506.
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Matre, Dagfinn, and Stein Knardahl. "‘Central sensitization’ in chronic neck/shoulder pain." Scandinavian Journal of Pain 3, no. 4 (October 1, 2012): 230–35. http://dx.doi.org/10.1016/j.sjpain.2012.04.003.
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AbstractBackground and purpose‘Central sensitization’ (CS) may play a major role in maintaining several chronic pain conditions. CS has been proposed to play a significant role in a range of musculoskeletal pain conditions, such as trapezius myalgia, fibromyalgia, temporomandibular disorders, and low back pain. Whether CS varies over time within an individual is not known. This study evaluated (1) whether there is an intraindividual association between clinical pain and signs of CS, and (2) whether there is an inter-individual association between clinical pain and signs of CS.MethodsTwenty-seven sedentary workers (19 women, 8 men) with varying neck/shoulder pain participated in a pre-test and in two test sessions. On one of the test sessions the subjects had weak (or no) clinical pain (weak-pain day). On the other test session the subjects had stronger clinical pain (strong-pain day). As an indicator of ‘central sensitization’, we assessed the area of secondary pinprick hyperalgesia (tested by 84.4 g/mm2 Von Frey hairs) in response to a first-degree burn to the volar fore-arm (contact heat, 46°C, 5 min). While in the lab, the subjects’ current clinical pain intensity (0–10 cm VAS) and distribution was assessed (PINTlab and PDISTlab ). The subjects also rated their pain intensity and distribution retrospectively from the past 30 days (PINT30d and PDIST30d ).ResultsPINTlab was lower on the weak-pain day (1.7 ± 1.5 cm) than on the strong-pain day (4.3 ± 1.6 cm). This was also the case for the other clinical pain measures (PDISTlab, PINT30 d and PDIST30 d ) and indicated that the participants were successfully recruited at days that differed in clinical pain severity. Despite a significant intra-individual difference in clinical pain between days, the area of secondary hyperalgesia did not differ between weak-and strong-pain days (50.3 ± 13.5 cm2 vs. 51.2 ± 12.6 cm2 ). Testing the inter-individual association between clinical pain and secondary hyperalgesia, we found a positive correlation between PINTlab and secondary hyperalgesia on the weak-pain day (rho = 0.6), but not on the strong-pain day (rho = 0.1). Given the stable secondary hyperalgesia across weak-and strong-pain days, this implies that subjects with a small secondary hyperalgesic area exhibited a relatively large variation in clinical pain between days, whereas subjects with a large secondary hyperalgesic area exhibited relatively small variation in clinical pain.ConclusionsWhen subjects are observed across days, ‘central sensitization’, measured as the area of secondary hyperalgesia after a first-degree burn, does not seem to be important for clinical pain intensity per se, but may be important for clinical pain variation. Subjects with indication of low ‘central sensitization’ seem to exhibit larger variation in pain between “good” and “bad” days than subjects with indication of high ‘central sensitization’. The study indicates that ‘central sensitization’ does not explain intra-individual variations in clinical pain.ImplicationsThis study raises the question of the role of ‘central sensitization’ in clinical musculoskeletal pain disorders. Furthermore, a precise definition of the ‘central sensitization’ concept is called for.
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Greco, Rosaria, Chiara Demartini, Anna Maria Zanaboni, Elisa Redavide, Selena Pampalone, Joseph Toldi, Ferenc Fülöp, et al. "Effects of kynurenic acid analogue 1 (KYNA-A1) in nitroglycerin-induced hyperalgesia: Targets and anti-migraine mechanisms." Cephalalgia 37, no. 13 (November 16, 2016): 1272–84. http://dx.doi.org/10.1177/0333102416678000.
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Background Trigeminal sensitization represents a major mechanism underlying migraine attacks and their recurrence. Nitroglycerin (NTG) administration provokes spontaneous migraine-like headaches and in rat, an increased sensitivity to the formalin test. Kynurenic acid (KYNA), an endogenous regulator of glutamate activity and its analogues attenuate NTG-induced neuronal activation in the nucleus trigeminalis caudalis (NTC). The anti-hyperalgesic effect of KYNA analogue 1 (KYNA-A1) was investigated on animal models specific for migraine pain. Aim Rats made hyperalgesic by NTG administration underwent the plantar or orofacial formalin tests. The effect of KYNA-A1 was evaluated in terms of nocifensive behavior and of neuronal nitric oxide synthase (nNOS), calcitonin gene-related peptide (CGRP) and cytokines expression in areas involved in trigeminal nociception. Results KYNA-A1 abolished NTG-induced hyperalgesia in both pain models; NTG alone or associated to formalin injection induced an increased mRNA expression of CGRP, nNOS and cytokines in the trigeminal ganglia and central areas, which was reduced by KYNA-A1. Additionally, NTG caused a significant increase in nNOS immunoreactivity in the NTC, which was prevented by KYNA-A1. Conclusion Glutamate activity is likely involved in mediating hyperalgesia in an animal model specific for migraine. Its inhibition by means of a KYNA analogue modulates nNOS, CGRP and cytokines expression at peripheral and central levels.
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Iannetti, G. D., U. Baumgärtner, I. Tracey, R. D. Treede, and W. Magerl. "Pinprick-evoked brain potentials: a novel tool to assess central sensitization of nociceptive pathways in humans." Journal of Neurophysiology 110, no. 5 (September 1, 2013): 1107–16. http://dx.doi.org/10.1152/jn.00774.2012.
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Although hyperalgesia to mechanical stimuli is a frequent sign in patients with inflammation or neuropathic pain, there is to date no objective electrophysiological measure for its evaluation in the clinical routine. Here we describe a technique for recording the electroencephalographic (EEG) responses elicited by mechanical stimulation with a flat-tip probe (diameter 0.25 mm, force 128 mN). Such probes activate Aδ nociceptors and are widely used to assess the presence of secondary hyperalgesia, a psychophysical correlate of sensitization in the nociceptive system. The corresponding pinprick-evoked potentials (PEPs) were recorded in 10 subjects during stimulation of the right and left hand dorsum before and after intradermal injection of capsaicin into the right hand and in 1 patient with a selective lesion of the right spinothalamic tract. PEPs in response to stimulation of normal skin were characterized by a vertex negative-positive (NP) complex, with N/P latencies and amplitudes of 111/245 ms and 3.5/11 μV, respectively. All subjects developed a robust capsaicin-induced increase in the pain elicited by pinprick stimulation of the secondary hyperalgesic area (+91.5%, P < 0.005). Such stimulation also resulted in a significant increase of the N-wave amplitude (+92.9%, P < 0.005), but not of the P wave (+6.6%, P = 0.61). In the patient, PEPs during stimulation of the hypoalgesic side were reduced. These results indicate that PEPs 1) reflect cortical activities triggered by somatosensory input transmitted in Aδ primary sensory afferents and spinothalamic projection neurons, 2) allow quantification of experimentally induced secondary mechanical hyperalgesia, and 3) have the potential to become a diagnostic tool to substantiate mechanical hyperalgesia in patients with presumed central sensitization.
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Sweeney, Marva Irene, and J. Ana Sawynok. "Evidence that substance P may be a modulator rather than a transmitter of noxious mechanical stimulation." Canadian Journal of Physiology and Pharmacology 64, no. 10 (October 1, 1986): 1324–27. http://dx.doi.org/10.1139/y86-224.
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Substance P (SP), injected intrathecally, produced a dose-related increase in responsiveness (hyperalgesia) in a pressure test for nociceptive thresholds. Pretreatment with two doses of SP produced complete desensitization to this response but did not alter base-line responsiveness. The hyperalgesic response to SP and the lack of change in base line following desensitization to SP suggest a modulator rather than a transmitter role for SP in the transmission of noxious mechanical stimulation.
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Yates, Darran. "Reversing hyperalgesia." Nature Reviews Neuroscience 15, no. 8 (July 18, 2014): 495. http://dx.doi.org/10.1038/nrn3790.
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Asaro, Joseph, Christine A. Robinson, and Philip T. Levy. "Visceral Hyperalgesia." Child Neurology Open 4 (January 1, 2017): 2329048X1769312. http://dx.doi.org/10.1177/2329048x17693123.
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Visceral hyperalgesia refers to increased pain sensation in response to gastrointestinal sensory stimulus. In neonates with neurological impairments, gabapentin has been successfully used as a treatment for visceral hyperalgesia in neonates. The authors describe a preterm infant with myelomeningocele and persistent neuropathic pain that manifested as irritability, hypertonicity, poor weight gain, and feeding intolerance. After exclusion of other etiologies, the diagnosis of visceral hyperalgesia was suspected and the infant was treated with gabapentin. Following appropriate titration to effect and close monitoring of side effects of gabapentin, he subsequently demonstrated improved tone, decreased irritability with feedings, and appropriate weight gain. In addition, the authors provide a review of the available literature of gabapentin use in neonates and offer suggestions on when to consider starting gabapentin in a neonate with neurological impairment and chronic unexplained gastrointestinal manifestations.
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Touil, Nassim, and Patricia Lavand’homme. "Cannabis hyperalgesia." European Journal of Anaesthesiology 36, no. 9 (September 2019): 623–24. http://dx.doi.org/10.1097/eja.0000000000001025.
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Bannister, Kirsty, and Anthony H. Dickenson. "Opioid hyperalgesia." Current Opinion in Supportive and Palliative Care 4, no. 1 (March 2010): 1–5. http://dx.doi.org/10.1097/spc.0b013e328335ddfe.
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Fillingim, R., L. Kaplan, R. Staud, T. Ness, T. Glover, C. Campbell, J. Mogil, and M. Wallace. "Psychophysics/hyperalgesia." Journal of Pain 5, no. 3 (April 2004): S31. http://dx.doi.org/10.1016/j.jpain.2004.02.090.
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Kaplan, L., R. Fillingim, M. Agbandje-McKenna, R. Staud, T. Glover, C. Campbell, J. Mogil, and M. Wallace. "Psychophysics/hyperalgesia." Journal of Pain 5, no. 3 (April 2004): S31. http://dx.doi.org/10.1016/j.jpain.2004.02.091.
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Scanlon, G., J. Ispirescu, M. Wallace, and G. Schulteis. "Psychophysics/hyperalgesia." Journal of Pain 5, no. 3 (April 2004): S31. http://dx.doi.org/10.1016/j.jpain.2004.02.092.
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Doherty, J., L. Zambreanu, J. Brooks, and I. Tracey. "Psychophysics/hyperalgesia." Journal of Pain 5, no. 3 (April 2004): S32. http://dx.doi.org/10.1016/j.jpain.2004.02.093.
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Quevedo, A., and R. Coghill. "Psychophysics/hyperalgesia." Journal of Pain 5, no. 3 (April 2004): S32. http://dx.doi.org/10.1016/j.jpain.2004.02.094.
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Wilder-Smith, Oliver H. G., and Lars Arendt-Nielsen. "Postoperative Hyperalgesia." Anesthesiology 104, no. 3 (March 1, 2006): 601–7. http://dx.doi.org/10.1097/00000542-200603000-00028.
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Prasad, Garrepally. "Ameliorate Inflammatory Hyperalgesia in the Rat." Journal of Clinical and Medical Case Reports and Reviews 1, no. 1 (December 30, 2021): 1–3. http://dx.doi.org/10.59468/2837-469x/005.
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Background: Proteins insulated from the latex (LP) of Calotropis procera (family Apocynaceae) have been shown to meliorate seditious hyperalgesia in the rat model of Freund's Complete Adjuvant (FCA) convinced monoarthritis. The ideal of the present study was to estimate the effect of LP on inflammation indicator and time of functional recovery in arthritic rats. Methods: Monoarthritis was convinced byintra-articular injection of FCA and common periphery, motility, stair climbing capability and rearward flexion pain scores were recorded before converting arthritis and later at different time intervals till common functions recovered (day 16). The area under wind (AUC) for increase in common periphery was calculated. The rats were offered and the towel situations of reduced glutathione and thiobarbituric acid reactive substances were measured. Histological analysis of the joint was also carried out. The effect of LP (5 and 25 mg/ kg) and diclofenac (5 mg/ kg) given on alternate days was estimated on the parameters mentioned. Results: LP produced a cure-dependent reduction in AUC for increase in common periphery and the time needed to attain the normal common functions as compared to the arthritic controls. Treatment with LP regularized the situations of oxidative stress labels and saved towel armature. The protection swung by LP was similar to that with diclofenac. Conclusion: The present study shows that by inhibiting inflammation, LP bit of latex ofC. procera ameliorates functional limitations in arthritic rats.
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Taylor, Bradley K., Robyn E. Roderick, Elizabeth St. Lezin, and Allan I. Basbaum. "Hypoalgesia and hyperalgesia with inherited hypertension in the rat." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 280, no. 2 (February 1, 2001): R345—R354. http://dx.doi.org/10.1152/ajpregu.2001.280.2.r345.
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Many studies indicate that blood pressure control systems can attenuate pain (hypoalgesia) of short duration; however, we recently found exaggerated nociceptive responses (hyperalgesia) of persistent duration in the spontaneously hypertensive rat (SHR). Here, we used SHR, Dahl Salt-Sensitive (SS), and normotensive control rats to evaluate the contribution of sustained elevations in arterial pressure to nociceptive responses. Compared with Sprague-Dawley and/or Wistar-Kyoto controls, SHR were 1) hypoalgesic in the hot plate test and 2) hyperalgesic in longer latency tail and paw-withdrawal tests and in two models of inflammatory nociception. These differences were not observed between SS and salt-resistant controls fed a high-salt diet. Inflammatory hyperalgesia in SHR was correlated with neither paw edema nor the number of Fos-positive spinal cord neurons. Our results indicate that “pain” phenotype of the SHR is not restricted to hypoalgesia. This phenotype is related to genetic factors or to the autonomic systems that control blood pressure and not to sustained elevations in blood pressure, differences in spinal neuron activity, or inflammatory edema.
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Bosnjak, Zeljko J., Esther M. Pogatzki, Mark O. Urban, Timothy J. Brennan, and Gerald F. Gebhart. "Role of the Rostral Medial Medulla in the Development of Primary and Secondary Hyperalgesia after Incision in the Rat." Anesthesiology 96, no. 5 (May 1, 2002): 1153–60. http://dx.doi.org/10.1097/00000542-200205000-00019.
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Background Descending influences from the rostral medial medulla (RMM) contribute to secondary hyperalgesia in persistent inflammatory, neuropathic, and visceral pain models. The current study examined if descending inhibition or facilitation from the RMM modulates primary and secondary hyperalgesia after incision in the rat hind limb. Methods Bilateral RMM lesions were produced using the soma-selective neurotoxin ibotenic acid, and the effect of RMM lesion was examined on primary and secondary hyperalgesia 5 days after a plantar or gastrocnemius incision, respectively. Results Plantar incision reduced withdrawal thresholds to von Frey filaments applied adjacent to the incision (primary punctate hyperalgesia). The withdrawal thresholds were the same in RMM-lesioned and sham-operated rats. The response frequency to a blunt mechanical stimulus after plantar incision was increased (primary nonpunctate hyperalgesia) in both groups. Nonpunctate hyperalgesia was greater in lesioned rats on postoperative day 2 only; all other measures were not different. Primary heat hyperalgesia after plantar incision was not modulated by RMM lesion. Secondary punctate hyperalgesia after gastrocnemius incision was not affected by RMM lesion. Gastrocnemius incision did not produce secondary nonpunctate or heat hyperalgesia in either RMM lesion or sham rats. Conclusion Primary and secondary hyperalgesia after an incision were not modulated by descending influence from the RMM. The lack of contribution of descending facilitatory influences from the RMM to secondary hyperalgesia after gastrocnemius incision supports the notion that incision-induced pain involves dissimilar mechanisms compared with inflammatory and neuropathic pain.
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Dirks, Jesper, Steen Møiniche, Karen-Lisa Hilsted, and Jørgen B. Dahl. "Mechanisms of Postoperative Pain: Clinical Indications for a Contribution of Central Neuronal Sensitization." Anesthesiology 97, no. 6 (December 1, 2002): 1591–96. http://dx.doi.org/10.1097/00000542-200212000-00035.
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Background The relative importance of different nociceptive mechanisms for the intensity, duration, and character of postoperative pain is not well established. It has been suggested that sensitization of dorsal horn neurones may contribute to pain in the postoperative period. We hypothesized that wound hyperalgesia in postoperative patients and experimentally heat-induced secondary hyperalgesia share a common mechanism, sensitization of central neurones, and consequently, that the short-acting opioid remifentanil would have comparable effects on hyperalgesia in both conditions. Methods In a randomized, controlled, double-blind trial, we assessed mechanical hyperalgesia in skin bordering the surgical wound, and an area of experimentally heat-induced secondary hyperalgesia on the thigh, in 12 patients who underwent abdominal hysterectomy within 5 days prior to the investigation. Observations were made before and during a drug challenge with remifentanil, which has been demonstrated to reduce the area of heat-induced secondary hyperalgesia in volunteers. Results The area of skin with surgically-induced mechanical hyperalgesia, the area of heat-induced secondary hyperalgesia, and pain during cough, were significantly reduced during remifentanil infusion compared with placebo (P = 0.008, P = 0.006, and P = 0.002, respectively). The relative reduction (% of baseline) of the area of skin with surgically-induced hyperalgesia and heat-induced secondary hyperalgesia during infusion of remifentanil was significantly associated (R2 = 0.72, P = 0.001). Conclusions Although remifentanil is not a highly targeted "antihyperalgesic," these results support the hypothesis that both wound hyperalgesia in postoperative patients and experimentally heat-induced secondary hyperalgesia may share common mechanisms, and that central neuronal sensitization may contribute to some aspects of postoperative pain. Antihyperalgesic drugs should be further developed and evaluated in clinical trials of postoperative pain.
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Perkins, M. N., D. Kelly, and A. J. Davis. "Bradykinin B1 and B2 receptor mechanisms and cytokine-induced hyperalgesia in the rat." Canadian Journal of Physiology and Pharmacology 73, no. 7 (July 1, 1995): 832–36. http://dx.doi.org/10.1139/y95-113.
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The involvement of bradykinin (BK) B1 and B2 receptors in cytokine-induced hyperalgesia has been studied in the rat. Intraplantar injections of interleukin (IL) 1β and tumor necrosis factor α (TNFα) induced thermal hyperalgesia, with in the the case of IL-1β, contralateral hyperalgesia also present. Subsequent to administration of IL-1β, but not after TNFα, des-Arg9-BK reduced the withdrawal latency in both ipsi- and contra-lateral paws. Mechanical hyperalgesia was also induced by IL-1β, IL-2, and IL-8 when injected into rat knee joints, whereas IL-6 and TNFα were without effect. Coadministration of des-Arg9,Leu8-BK prevented the development of the cytokine-induced hyperalgesia for the duration of the experiment (6 h), but HOE-140 only reversed the hyperalgesia for the 1st h. At 3.5 h after IL-1β, IL-2, or IL-8, administration of des-Arg9,Leu8-BK or HOE-140 (iv) completely reversed the hyperalgesia. Twenty-four hours after pretreatment with IL-1β, injection of des-Arg9-BK into the joint produced opposite effects, depending on the dose: at 50 pmol the hyperalgesia was reversed, but at 0.5 nmol there was further hyperalgesia. Both responses were blocked by B1 but not B2 receptor antagonists. These data suggest that both B1 and B2 receptors are involved in the induction and maintenance of cytokine-induced hyperalgesia. B1 receptors appear to play a more important role than B2 receptors in the development of mechanical hyperalgesia.Key words: interleukin 1β, interleukin 2, interleukin 6, interleukin 8, tumor necrosis factor α, bradykinin, des-Arg9-bradykinin, bradykinin receptors, hyperalgesia, inflammation.
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Ülger, Gülay, H. Volkan Acar, Ramazan Baldemir, Esma Tezer, Ahmet Yilmaz, S. Aysegul Ertaskin, and Bayazit Dikmen. "The Effect of Pre-incisional and Post-incisional Acupuncture on Hyperalgesia in Rat Incision Model." Acupuncture & Electro-Therapeutics Research 46, no. 4 (August 24, 2021): 345–56. http://dx.doi.org/10.3727/036012921x16237619666030.
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Postoperative pain cannot be treated adequately in all patients, even though there are new developments in analgesic agents and treatment techniques. Thisstudy investigates the effect of pre-incisional and post-incisional electro- acupuncture on mechanical hyperalgesia in rat incisional pain model. This study was carried out with 40 healthy Sprague-Dawley male rats. The rats were divided into 5 groups: Group 1; first electro-acupuncture, then incision. Group 2; first incision, then electro-acupuncture. Group 3; first sham electro-acupuncture, then incision. Group 4; first incision, then sham electro-acupuncture. Group 5; control (incision only). Electro-acupuncture was applied to the ST36 and SP6 acupuncture points on the right hind paw. Sham electro- acupuncture was applied to the right thigh. Von Frey filaments were used to measure hyperalgesia at baseline and at 4th, 6th, 24th and 48th hours. Shapiro Wilk test was used to determine whether the distribution of continuous variables was close to normal. Levene's test was used for homogeneity of variances. Bonferroni Correction Wilcoxon Sign test was used to determine whether the differences between follow-up times were statistically significant or not. Bonferroni Correction on Kruskal Wallis test was used to determine whether there was any difference between groups. If the Kruskal Wallis test statistics were significant, analysis was performed using Conover's multiple comparison test. p<0.05 was considered statistically significant. This study found that electro-acupuncture decreases hyperalgesia, and there was no significant difference between pre-incisional and post-incisional application in terms of the anti-hyperalgesic effectiveness of electro-acupuncture, except for the duration of action. Pre-incisional applications are more effective than post-incisional applications. Pre-incisional sham electro-acupuncture has also been found to have anti-hyperalgesic effect. Our findings support the studies that electro-acupuncture can be used for preemptive purposes in surgical patients. We think that researches should be continued in order to provide alternative methods for pain treatment.
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Jensen, Karin, Irving Kirsch, Sara Odmalm, Ted J. Kaptchuk, and Martin Ingvar. "Classical conditioning of analgesic and hyperalgesic pain responses without conscious awareness." Proceedings of the National Academy of Sciences 112, no. 25 (May 15, 2015): 7863–67. http://dx.doi.org/10.1073/pnas.1504567112.
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Pain reduction and enhancement can be produced by means of conditioning procedures, yet the role of awareness during the acquisition stage of classical conditioning is unknown. We used psychophysical measures to establish whether conditioned analgesic and hyperalgesic responses could be acquired by unseen (subliminally presented) stimuli. A 2 × 2 factorial design, including subliminal/supraliminal exposures of conditioning stimuli (CS) during acquisition/extinction, was used. Results showed significant analgesic and hyperalgesic responses (P < 0.001), and responses were independent of CS awareness, as subliminal/supraliminal cues during acquisition/extinction led to comparable outcomes. The effect was significantly larger for hyperalgesic than analgesic responses (P < 0.001). Results demonstrate that conscious awareness of the CS is not required during either acquisition or extinction of conditioned analgesia or hyperalgesia. Our results support the notion that nonconscious stimuli have a pervasive effect on human brain function and behavior and may affect learning of complex cognitive processes such as psychologically mediated analgesic and hyperalgesic responses.