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PubMed1999

Primary and secondary hyperalgesia in a rat model for human postoperative pain.

BACKGROUND: Previously, the authors developed and characterized a rat model for postoperative pain to learn more about pain produced by incisions. In this study, the responses to heat and mechanical stimuli were evaluated directly on or adjacent to the incision and at varying distances from the incision. METHODS: Rats were anesthetized with halothane and incisions were made at different locations in the plantar aspect of the foot. The response frequency to a blunt mechanical stimulus, the withdrawal threshold to von Frey filaments (15-522 mN), and the withdrawal latency to radiant heat were measured. Rats were tested before surgery, 2 h later, and then daily through postoperative day 9. RESULTS: After plantar incision, persistent hyperalgesia was observed immediately adjacent to or directly on the incision to punctate and blunt mechanical stimuli, respectively. The withdrawal threshold to punctate stimuli applied 1 cm from the incision was decreased through postoperative day 1. In a transitional area, between the distant and adjacent sites, the withdrawal threshold was intermediate and the duration of hyperalgesia was transient. Heat hyperalgesia was persistent but present when the stimulus was applied to the site of injury but not to a distant site. CONCLUSION: Robust primary hyperalgesia to punctate and blunt mechanical stimuli was present. Hyperalgesia distant to the wound, or secondary hyperalgesia, occurred in response to punctate mechanical stimuli, was short-lived, and required greater forces. These results suggest that the most persistent pain behaviors in this model are largely primary hyperalgesia.

Anesthetics, Inhalation↗
PubMed1999

The effect of naloxone on ketamine-induced effects on hyperalgesia and ketamine-induced side effects in humans.

BACKGROUND: The (NMDA) receptor plays a significant role in wind-up and spinal hypersensitivity and is involved in the occurrence of secondary hyperalgesia. Ketamine is an NMDA-receptor antagonist and has proven effective in alleviating secondary hyperalgesia in humans. Although it is disputed, the actions of ketamine have been ascribed not only to NMDA receptor antagonism, but also to opioid receptor agonism. A study therefore was designed in which the abolishment of a previously demonstrated effect of ketamine on secondary hyperalgesia was sought by pretreatment with naloxone. METHODS: Twenty-five volunteers were subjected to three treatment regimens. A standardized first-degree burn injury was induced. On appearance of primary and secondary hyperalgesia, one of the following infusion schemes was applied in a randomized, double-blind, cross-over fashion: (1) infusion of naloxone (0.8 mg/15 min followed by 0.4 mg/h), succeeded by infusion of ketamine (0.3 mg x kg(-1) x 15 min(-1) followed by 0.3 mg x kg(-1) x h(-1)); (2) infusion of placebo, succeeded by infusion of ketamine (0.3 mg x kg(-1) x 15 min(-1) followed by 0.3 mg x kg(-1) x h(-1)); and (3) infusion of placebo, succeeded by infusion of placebo. Heat-pain detection thresholds, magnitude of secondary hyperalgesia around the burn injury, and side effects were determined. RESULTS: Ketamine reduced secondary hyperalgesia. Naloxone did not affect the action of ketamine. The magnitudes of side effects were equal if the subjects received ketamine, regardless of preceding infusion of naloxone. CONCLUSIONS: In this experimental setting, opioid receptor blockade does not inhibit ketamine-induced reductions of secondary hyperalgesia.

Cross-Over Studies↗
PubMed2002

Fentanyl enhancement of carrageenan-induced long-lasting hyperalgesia in rats: prevention by the N-methyl-D-aspartate receptor antagonist ketamine.

BACKGROUND: Tissue damage may produce hyperalgesia, allodynia, and persistent pain. The authors recently reported that fentanyl elicits analgesia but also activates N-methyl-D-aspartate-dependent pain facilitatory processes opposing analgesia. In nonsuffering rats, this leads to a long-lasting enhancement in pain sensitivity. The current study assessed whether fentanyl could amplify carrageenan-induced hyperalgesia. METHODS: First, rats were injected once with carrageenan in a hind paw, with fentanyl (60 or 100 microg/kg each given four times at 15-min intervals [4 x 60 or 4 x100]) or saline. Second, rats were injected with carrageenan twice without fentanyl (7-day interval), with the second injection either in the previously injected paw or in the other paw. Third, rats were injected twice with carrageenan in the same hind paw: the first ketamine injection was given (10 mg/kg each given three times at 5-h intervals) with or without fentanyl (4 x 60 microg/kg), and second injection was given without ketamine or fentanyl. The consequences of treatments on long-term hyperalgesia were examined by the paw-pressure vocalization test. RESULTS: The long-lasting hyperalgesia induced by the first carrageenan injection was dose-dependently enhanced in both duration and magnitude in 4 x 60 or 4 x 100 microg/kg fentanyl-treated rats: 5 or 10 days, respectively, as compared with 2 days in saline-treated rats. Hyperalgesia observed in the hind paw contralateral to the first carrageenan injection was enhanced in fentanyl-treated rats. The second carrageenan injection, performed in any hind paw, induced an exaggerated hyperalgesia, especially in fentanyl-treated rats. Pretreatment with ketamine totally prevented the carrageenan- and fentanyl-induced enhancement of the long-lasting hyperalgesia. CONCLUSION: Central sensitization in inflammatory pain states is reinforced by an opiate treatment, which could be prevented by N-methyl-D-aspartate receptors blockade.

Analgesics, Opioid↗
PubMed2004

Hyperalgesia in outpatients with dermal injury: quantitative sensory testing versus a novel simple technique.

OBJECTIVE: Dermal inflammation from many causes may produce a reversible period of hyperalgesia (increased sensitivity to pain perception) or allodynia (pain from innocuous stimuli). Hyperalgesia and allodynia have received relatively little attention in clinical trials of acute pain. We sought to quantitate tactile allodynia and thermal hyperalgesia in outpatients presenting with acute dermal injuries. DESIGN: We performed a randomized clinical trial to compare standard methodology for the assessment of hyperalgesia with two novel simple quantitative techniques. PATIENTS: After Institutional Review Board approval, 40 patients presenting with acute chemical, thermal, mechanical, or infectious skin injury were subjected to a series of tests at the site of injury, an intact mirror site, and a noninjured ipsilateral control site. OUTCOME MEASURES: Quantitative thermal sensory testing (Medoc sensory analyzer) was followed by a 5-second application, in random order, of copper rods preheated in water to 40 degrees C, 43 degrees C, 46 degrees C, and 49 degrees C. Pressure testing was conducted with a 1.25-inch diameter commercially available pressure transducer gauge. RESULTS: The observed pattern of responses was remarkably consistent among testing methods. All challenges with the four different temperatures elicited pain scores on a visual analog scale markedly greater at the injured than at the mirror or control site (P < 0.001 vs control). Pressure discomfort thresholds followed a similar pattern. CONCLUSIONS: We conclude that hyperalgesia is a prominent contributor to discomfort in acute dermal injury and hence is a legitimate therapeutic target. Quantitation of the contribution of thermal hyperalgesia and tactile allodynia and assessment of their management is feasible using simple, rugged, low-cost methods. This inexpensive methodology may be useful in everyday clinical practice as well as in clinical research evaluating pharmacological agents to manage hyperalgesia.

Adolescent↗
PubMed1992

Central changes in processing of mechanoreceptive input in capsaicin-induced secondary hyperalgesia in humans.

1. Capsaicin, the algesic substance in chilli peppers, was injected intradermally in healthy human subjects. A dose of 100 micrograms given in a volume of 10 microliters caused intense pain lasting for a few minutes after injection and resulted in a narrow area of hyperalgesia to heat and a wide surrounding area of hyperalgesia to mechanical stimuli (stroking) lasting for 1-2 h. 2. Nerve compression experiments with selective block of impulse conduction in myelinated (A) but not in unmyelinated (C) fibres indicated that afferent signals in C fibres contributed to pain from capsaicin injection and to heat hyperalgesia, whereas conduction in afferent A fibres was necessary for the perception of mechanical hyperalgesia. 3. Electrical intraneural microstimulation normally eliciting non-painful tactile sensations was accompanied by pain when the sensation was projected to skin areas within the region of mechanical hyperalgesia induced by capsaicin injection. 4. The threshold for pain evoked by intraneural microstimulation was reversibly lowered and pain from suprathreshold stimulation was exaggerated during the period of mechanical hyperalgesia, regardless of lidocaine anaesthesia of the cutaneous innervation territory of the stimulated fibres. 5. The results indicate that hyperalgesia to stroking on a skin area surrounding a painful intradermal injection of capsaicin is due to reversible changes in the central processing of mechanoreceptive input from myelinated fibres which normally evoke non-painful tactile sensations.

Adult↗
PubMed2006

Protease-activated receptor 2 sensitizes the transient receptor potential vanilloid 4 ion channel to cause mechanical hyperalgesia in mice.

Exacerbated sensitivity to mechanical stimuli that are normally innocuous or mildly painful (mechanical allodynia and hyperalgesia) occurs during inflammation and underlies painful diseases. Proteases that are generated during inflammation and disease cleave protease-activated receptor 2 (PAR2) on afferent nerves to cause mechanical hyperalgesia in the skin and intestine by unknown mechanisms. We hypothesized that PAR2-mediated mechanical hyperalgesia requires sensitization of the ion channel transient receptor potential vanilloid 4 (TRPV4). Immunoreactive TRPV4 was coexpressed by rat dorsal root ganglia (DRG) neurons with PAR2, substance P (SP) and calcitonin gene-related peptide (CGRP), mediators of pain transmission. In PAR2-expressing cell lines that either naturally expressed TRPV4 (bronchial epithelial cells) or that were transfected to express TRPV4 (HEK cells), pretreatment with a PAR2 agonist enhanced Ca2+ and current responses to the TRPV4 agonists phorbol ester 4alpha-phorbol 12,13-didecanoate (4alphaPDD) and hypotonic solutions. PAR2-agonist similarly sensitized TRPV4 Ca2+ signals and currents in DRG neurons. Antagonists of phospholipase Cbeta and protein kinases A, C and D inhibited PAR2-induced sensitization of TRPV4 Ca2+ signals and currents. 4alphaPDD and hypotonic solutions stimulated SP and CGRP release from dorsal horn of rat spinal cord, and pretreatment with PAR2 agonist sensitized TRPV4-dependent peptide release. Intraplantar injection of PAR2 agonist caused mechanical hyperalgesia in mice and sensitized pain responses to the TRPV4 agonists 4alphaPDD and hypotonic solutions. Deletion of TRPV4 prevented PAR2 agonist-induced mechanical hyperalgesia and sensitization. This novel mechanism, by which PAR2 activates a second messenger to sensitize TRPV4-dependent release of nociceptive peptides and induce mechanical hyperalgesia, may underlie inflammatory hyperalgesia in diseases where proteases are activated and released.

Animals↗
PubMed2004

Intrathecal protease-activated receptor stimulation produces thermal hyperalgesia through spinal cyclooxygenase activity.

Activation of protease-activated receptors (PARs) in non-neural tissue results in prostaglandin production. Because PARs are found in the spinal cord and increased prostaglandin release in the spinal cord causes thermal hyperalgesia, we hypothesized that activation of these spinal PARs would stimulate prostaglandin production and cause a cyclooxygenase-dependent thermal hyperalgesia. PARs were activated using either thrombin or peptide agonists derived from the four PAR subtypes, delivered to the lumbar spinal cord. Dialysis experiments were conducted in conscious, unrestrained rats using loop microdialysis probes placed in the lumbar intrathecal space. Intrathecal thrombin stimulated release of prostaglandin E (PGE)(2) but not aspartate or glutamate. Intrathecal delivery of the PAR 1-derived peptide SFLLRN-NH(2) and the PAR 2-derived peptide SLIGRL both stimulated PGE(2) release; PAR 3-derived TFRGAP and PAR 4-derived GYPGQV were inactive. Intrathecal thrombin had no effect upon formalin-induced flinching or tactile sensitivity but resulted in a thermal hyperalgesia. Intrathecal SFLLRN-NH(2) and SLIGRL both produced thermal hyperalgesia. Consistent with their effects on spinal PGE(2), hyperalgesia from these peptides was blocked by pretreatment with the cyclooxygenase inhibitor ibuprofen. SLIGRL-induced hyperalgesia was also blocked by the selective inhibitors SC 58,560 [5-(4-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole; cyclooxygenase (COX) 1] and SC 58,125 [5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole; COX 2]. These data indicate that activation of spinal PAR 2 and possibly PAR 1 results in the stimulation of the spinal cyclooxygenase cascade and a prostaglandin-dependent thermal hyperalgesia.

Animals↗
PubMed1999

Epinephrine produces a beta-adrenergic receptor-mediated mechanical hyperalgesia and in vitro sensitization of rat nociceptors.

Hyperalgesic and nociceptor sensitizing effects mediated by the beta-adrenergic receptor were evaluated in the rat. Intradermal injection of epinephrine, the major endogenous ligand for the beta-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 beta-adrenergic receptor antagonist, but not by phentolamine, an alpha-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 beta-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 mu-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 beta-adrenergic receptor. These effects of epinephrine are mediated by both the protein kinase A and protein kinase C second-messenger pathways.

Analysis of Variance↗
PubMed1997

Effects of various analgesic and anti-inflammatory drugs on endotoxin-induced hyperalgesia in rats and mice.

A new model of endotoxin (ET)-induced hyperalgesia has been used to test the effects of four classes of drugs in rats and mice. Hyperalgesia was assessed by paw pressure (PP), hot plate (HP) and tail flick (TF) tests. Each drug was injected intraperitoneally 24 and 12 h before ET injection and just before each pain test at 3, 6, 9 and 24 h after ET injection. At the dosages used, acetaminophen and dexamethasone were the most effective in reducing PP hyperalgesia and least effective on TF hyperalgesia, while indometacin and morphine produced their main effect on TF hyperalgesia. The four drugs were about equally effective in reversing HP hyperalgesia. We conclude that ET hyperalgesia is mediated by both prostaglandin-sensitive and prostaglandin-independent mechanisms.

Acetaminophen↗
PubMed2004

Effect of selective inhibition of cyclooxygenase-2 on lipopolysaccharide-induced hyperalgesia.

Lipopolysaccharide (LPS) is known to increase the expression and release of various pro-inflammatory mediators, including cyclooxygenase-2 (COX-2) and produce hyperalgesia. It is also well known that prostaglandins (PGs), synthesised both in the periphery and centrally by COX isoforms, play a key role in sensitisation of nociceptors and nociceptive processing. To investigate the role of COX-2 in LPS-induced hyperalgesia, parecoxib, a selective COX-2-inhibiting pro-drug, was injected intravenously 30 min before assessing hyperalgesia induced by intraperitoneal or subcutaneous administration of LPS (50 microg/mouse or 25 microg/paw of rat, respectively). Acetic acid-induced writhing and tail immersion assay in mice and paw withdrawal response to thermal and mechanical stimuli in rats were used to assess the effect of inhibition of COX-2 on LPSinduced hyperalgesia. Animals showed significant hyperalgesic behavior 8 h after LPS injection. Parecoxib (up to 20 mg/kg, i.v.) had no effect in the two acute nociceptive assays but showed marked antinociceptive activity in writhing and tail immersion assay in LPS-pretreated mice. Similarly, parecoxib reversed the hyperalgesia in the LPS-injected paw but not in the contralateral paw of rats. Pre-treatment with dexamethasone, an inhibitor of COX-2 expression before LPS injection significantly affected the development of hyperalgesia in both mice and rats. These findings suggest that inducible COX-2 derived PGs are involved in central nociceptive processing, which resulted in hyperalgesic behavior following LPS administration and inhibition of COX-2 or its expression attenuated LPS-induced hyperalgesia.

Animals↗
PubMed1999

Brain processing of capsaicin-induced secondary hyperalgesia: a functional MRI study.

OBJECTIVE: To investigate, using functional MRI (fMRI), the neural network that is activated by the pain component of capsaicin-induced secondary mechanical hyperalgesia. BACKGROUND: Mechanical hyperalgesia (i.e., pain to innocuous tactile stimuli) is a distressing symptom of neuropathic pain syndromes. Animal experiments suggest that alterations in central pain processing occur that render tactile stimuli capable of activating central pain-signaling neurons. A similar central sensitization can be produced experimentally with capsaicin. METHODS: In nine healthy individuals the cerebral activation pattern resulting from cutaneous nonpainful mechanical stimulation at the dominant forearm was imaged using fMRI. Capsaicin was injected adjacent to the stimulation site to induce secondary mechanical hyperalgesia. The identical mechanical stimulation was then perceived as painful without changing the stimulus intensity and location. Both activation patterns were compared to isolate the specific pain-related component of mechanical hyperalgesia from the tactile component. RESULTS: The pattern during nonpainful mechanical stimulation included contralateral primary sensory cortex (SI) and bilateral secondary sensory cortex (SII) activity. During hyperalgesia, significantly higher activation was found in the contralateral prefrontal cortex: the middle (Brodmann areas [BAs] 6, 8, and 9) and inferior frontal gyrus (BAs 44 and 45). No change was present within SI, SII, and the anterior cingulate cortex. CONCLUSIONS: Prefrontal activation is interpreted as a consequence of attention, cognitive evaluation, and planning of motor behavior in response to pain. The lack of activation of the anterior cingulate contrasts with physiologic pain after C-nociceptor stimulation. It might indicate differences in the processing of hyperalgesia and C-nociceptor pain or it might be due to habituation of affective sensations during hyperalgesia compared with acute capsaicin pain.

Adult↗
PubMed2005

Neurotrophin-3 suppresses thermal hyperalgesia associated with neuropathic pain and attenuates transient receptor potential vanilloid receptor-1 expression in adult sensory neurons.

Neurotrophin-3 (NT-3) negatively modulates nerve growth factor (NGF) receptor expression and associated nociceptive phenotype in intact neurons, suggesting a beneficial role in treating aspects of neuropathic pain mediated by NGF. We report that NT-3 is effective at suppressing thermal hyperalgesia associated with chronic constriction injury (CCI); however, NT-3 does not alter the mechanical hypersensitivity that also develops with CCI. Thermal hyperalgesia is critically linked to expression and activation of the capsaicin receptor, transient receptor potential vanilloid receptor-1 (TRPV1). Thus, its modulation by NT-3 after CCI was examined. CCI results in elevated TRPV1 expression at both the mRNA and protein levels in predominantly small-to-medium neurons, with the percentage of neurons expressing TRPV1 remaining unchanged at approximately 56%. Attenuation of thermal hyperalgesia mediated by NT-3 correlates with decreased TRPV1 expression such that only approximately 26% of neurons ipsilateral to CCI expressed detectable TRPV1 mRNA. NT-3 effected a decrease in expression of the activated component of the signaling pathway linked to regulation of TRPV1 expression, phospho-p38 MAPK (Ji et al., 2002), in neurons ipsilateral to CCI. Exogenous NT-3 could both prevent the onset of thermal hyperalgesia and reverse established thermal hyperalgesia and elevated TRPV1 expression 1 week after CCI. Continuous infusion is required for suppression of both thermal hyperalgesia and TRPV1 expression, because removal of NT-3 resulted in a prompt reestablishment of the hyperalgesic state and corresponding CCI-associated TRPV1 phenotype. In conclusion, although NGF drives inflammation-associated thermal hyperalgesia via its regulation of TRPV1 expression, NT-3 is now identified as a potent negative modulator of this state.

Animals↗
PubMed2002

Evaluation of antivenoms in the neutralization of hyperalgesia and edema induced by Bothrops jararaca and Bothrops asper snake venoms.

Neutralization of hyperalgesia induced by Bothrops jararaca and B. asper venoms was studied in rats using bothropic antivenom produced at Instituto Butantan (AVIB, 1 ml neutralizes 5 mg B. jararaca venom) and polyvalent antivenom produced at Instituto Clodomiro Picado (AVCP, 1 ml neutralizes 2.5 mg B. aspar venom). The intraplantar injection of B. jararaca and B. asper venoms caused hyperalgesia, which peaked 1 and 2 h after injection, respectively. Both venoms also induced edema with a similar time course. When neutralization assays involving the independent injection of venom and antivenom were performed, the hyperalgesia induced by B. jararaca venom was neutralized only when bothropic antivenom was administered iv 15 min before venom injection, whereas edema was neutralized when antivenom was injected 15 min or immediately before venom injection. On the other hand, polyvalent antivenom did not interfere with hyperalgesia or edema induced by B. asper venom, even when administered prior to envenomation. The lack of neutralization of hyperalgesia and edema induced by B. asper venom is not attributable to the absence of neutralizing antibodies in the antivenom, since neutralization was achieved in assays involving preincubation of venom and antivenom. Cross-neutralization of AVCP or AVIB against B. jararaca and B. asper venoms, respectively, was also evaluated. Only bothropic antivenom partially neutralized hyperalgesia induced by B. asper venom in preincubation experiments. The present data suggest that hyperalgesia and edema induced by Bothrops venoms are poorly neutralized by commercial antivenoms even when antibodies are administered immediately after envenomation.

Animals↗
PubMed1993

Prostaglandin E2-induced thermal hyperalgesia and its reversal by morphine in the warm-water tail-withdrawal procedure in rhesus monkeys.

Four monkeys were seated in primate restraint chairs and the terminal 10 cm of their shaved tails were dipped into water maintained at a series of temperatures ranging from 38-54 degrees C. The latency to tail withdrawal from several temperatures was measured and temperature-effect curves for each monkey were generated. When administered s.c. into the tail, prostaglandin E2 (PGE2; 0, 1.58, 5.0 and 15.8 micrograms) produced a dose-dependent hyperalgesia manifested as dose-dependent leftward shifts in the temperature-effect curves. This hyperalgesia peaked 15 to 45 min after administration and lasted for approximately 2 hr. PGE2-induced hyperalgesia was mediated locally, because administration of 15.8 micrograms of PGE2 into the back had no effect on the temperature-effect curve. The hyperalgesic effects of PGE2 were reversed potently by morphine (0.32-3.2 mg/kg), and the effects of morphine were antagonized in a surmountable manner by both the opioid antagonist quadazocine (0.1 mg/kg) and by systemic administration of the charged opioid antagonist quaternary naltrexone (3.2 mg/kg). These results indicate that PGE2 produces thermal hyperalgesia in rhesus monkeys and also suggests that this hyperalgesia may be reversed by activation of peripheral opioid receptors. PGE2-induced hyperalgesia in the warm-water tail-withdrawal procedure may provide a useful assay for evaluating the effects of pharmacological and nonpharmacological treatments on hyperalgesia associated with inflammation in primates.

Animals↗
PubMed1997

Inheritable and acquired hyperalgesia associated to abnormal opioid receptor set-up seem to act as opiate addiction preventors.

Hyperalgesia is known to depend on neuroplastic changes chiefly represented by long-term potentiation. These phenomena are proved to depend on excitatory amino acids (EAAs) action at the level of NMDA receptors. This action is known to be related to nitric oxide (NO) release. We found a visceral/vascular hyperalgesia state in migraine (M) sufferers as well as an inheritable systemic hyperalgesia in healthy subjects who are first-degree consanguineous with M sufferers; this type was labelled 'third hyperalgesia'. We discovered that a hyper-increase of plasma L-citrulline, equimolar co-product in the synthesis of NO, characterizes both M sufferers and their first-degree relatives who are exempt from primary headache. A similar pattern never occurred in healthy subjects having both a personal and family history negative for primary headache. We conclude that both 'third hyperalgesia' and a pattern of NO synthase (NOS) hyperactivity seems to be inheritable and can constitute, at least in part, a ground for developing headache. Morphine, proved to be unable to relieve M attack, was given in low doses that caused pain and side-effects in M sufferers only. This outcome seemingly indicates that M sufferers are characterized by a set-up of opioid receptor subtypes different from that of healthy headache-exempts. Following a period of morphine addiction and a withdrawal period, 65.07% of a group of 63 opiate addicts developed M syndrome. All these subjects were first-degree consanguineous relatives of primary headache sufferers. Discussion topics concern the activity of morphine in NO release and the role of NO in sensory transmission of both controls and hyperalgesia sufferers. It is suggested that the inheritable couple consisting of hyperalgesia and NOS hyperactivity can play some role in setting off the pain occurring following morphine in M sufferers.

Adult↗
PubMed1998

Blockade of N- and P/Q-type calcium channels reduces the secondary heat hyperalgesia induced by acute inflammation.

High voltage calcium channels are implicated in nociceptive transmission after nerve injury, capsaicin or formalin injection. The purpose of this study was to investigate the role of calcium channels in secondary heat hyperalgesia associated with acute joint inflammation. After induction of acute inflammation (knee joint injection of kaolin and carrageenan), decreased paw withdrawal latency (PWL) to radiant heat (i.e., secondary heat hyperalgesia), increased guarding of the limb and increased joint circumference occurs. Spinal administration (through a microdialysis fiber placed in dorsal horn) of an N-type calcium channel blocker (MVIIA, SNX 111, ziconotide, 0.001-0.1 mM), before induction of inflammation, prevents the decrease in PWL. Treatment with SNX 111 4 hr after inflammation reverses heat hyperalgesia. A small reduction in spontaneous pain-related behaviors (guarding of the limb) occurs after pre- or post-treatment with SNX 111. Spinal blockade of P/Q-type calcium channels (with omega-agatoxin IVA) had no effect on the decrease in PWL to radiant heat when administered after induction of inflammation. However, pre-treatment with omega-agatoxin IVA prevents secondary heat hyperalgesia. omega-Agatoxin IVA has no effect on spontaneous pain-related behaviors whether administered before or after induction of inflammation. In contrast, pre or post-treatment with nifedipine (L-type calcium channel blocker, 0.01-1.0 mM), had no effect on heat hyperalgesia or spontaneous pain-related behaviors induced by acute inflammation. There were no differences in joint circumference between groups with any treatment. Thus, N-type calcium channels contribute to both the development and maintenance of secondary heat hyperalgesia while P-type calcium channels are only involved during development of hyperalgesia.

Animals↗
PubMed1989

The development of chronic mechanical hyperalgesia, autotomy and collateral sprouting following sciatic nerve section in rat.

The development of mechanical hyperalgesia over the tarsometatarsal joints subsequent to chronic sciatic section was studied in rats. Mechanical thresholds began to drop within 7 days of sciatic section and continued to decline for 2-3 weeks, resulting in significant hyperalgesia over the original saphenous and sciatic border zones lasting up to 310 days. Contralateral hyperalgesia, which is seen in tissue injury mechanical hyperalgesia, failed to develop. Collateral sprouting of high-threshold mechanoreceptors from the saphenous nerve into the denervated deep and cutaneous tissue was observed. The extent of cutaneous sprouting did not significantly correlate with the severity of hyperalgesia. The simultaneous uniform reduction of mechanical thresholds across all tarsometatarsal areas after chronic sciatic section is consistent with a central modulation of nociceptive afferent input. The severity and temporal development of the hyperalgesia strongly correlated with the extent of autotomy behavior. This animal model of chronic mechanical hyperalgesia following peripheral nerve section closely resembles a human neuropathic pain syndrome and may provide an experimental opportunity to advance our understanding of the neuropathology subserving chronic pain.

Animals↗
PubMed1993

Is large myelinated fiber loss associated with hyperalgesia in a model of experimental peripheral neuropathy in the rat?

Recently it has been shown that placement of 4 loose chromic gut sutures around the rat sciatic nerve produces hyperalgesia. A possible mechanism underlying this hyperalgesia is a preferential loss of large myelinated fibers. A difficulty, however, is that neuropathic symptoms are not static and the time course of the axon loss has not been determined. To remedy this deficit, the present study relates axonal changes to the behavior of the animal at various times after induction of the neuropathy. The findings are that a loss of all axon types, with a preferential loss of large myelinated axons, is associated with the development of heat hyperalgesia. As the axon loss progresses, however, the hyperalgesia lessens. In addition, at 28 days post surgery there are essentially no large myelinated axons in the distal segment, but the signs of hyperalgesia have almost resolved. These findings indicate that the onset of the hyperalgesia is accompanied by a preferential loss of large fibers and by a lesser but still substantial loss of small myelinated and unmyelinated axons. The subsequent course of the hyperalgesia, however, is not in any obvious way related to the proportions of large myelinated fibers in the affected nerve.

Animals↗