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PubMed2000

Allodynia and hyperalgesia induced by herpes simplex virus type-1 infection in mice.

Human subjects infected with herpes or varicella-zoster viruses complain of pain, such as allodynia, in or near the region with vesicles. However, the mechanisms of the pain are unclear. We show for the first time that infection with herpes simplex virus type-1 (HSV-1) induces allodynia and hyperalgesia in mice. When HSV-1 was inoculated on the hind paw of the mouse, eruption appeared on the back on day 5 post-inoculation, and zosteriform skin lesions were developed on the inoculated side. Allodynia and hyperalgesia became apparent in the hind paw on the inoculated side on day 5 and persisted until at least day 8. HSV-1 DNA was detected in the dorsal root ganglia from days 2 to 8 post-inoculation, with a peak effect on day 5. The application of heat-inactivated HSV-1 induced no allodynia, hyperalgesia and skin lesion. When started from days 0 or 2, repeated treatment with acyclovir, anti-HSV-1 agent, inhibited the appearance of allodynia, hyperalgesia, eruption and the viral proliferation in the dorsal root ganglia. In contrast, when started from days 5 or 6, acyclovir treatment slightly inhibited the development of skin lesions and the viral proliferation, but not allodynia and hyperalgesia. These results suggest that the propagation of HSV-1 in the dorsal root ganglia produces allodynia and hyperalgesia as a result of functional abnormality of the sensory neurons in mice. This may be a useful model for studying the mechanisms of herpetic pain.

Acyclovir↗
PubMed2000

Zinc in the extracellular area of the central nervous system is necessary for the development of kainic acid-induced persistent hyperalgesia in mice.

Kainic acid produces a persistent hyperalgesia when injected intraperitoneally (i.p.) in the rat or mouse. At higher doses than those needed to influence nociception, kainic acid induces seizures and translocation of histologically reactive zinc in the hippocampus. We tested the hypothesis that zinc, localized in a population of small diameter primary afferent neurons, plays a role in kainic acid-induced hyperalgesia similar to that in the hippocampus where zinc translocation accompanies kainic acid-induced seizures. The importance of zinc in the extracellular area was assessed by the influence of compounds that chelate divalent cations (disodium calcium ethylene diaminetetraacetate (CaEDTA)) or zinc (dipicolinic acid (DPA)) on kainic acid-induced hyperalgesia. When measured using the tail flick assay, thermal hyperalgesia was blocked by pretreatment intrathecally (i.t.) with either 10 nmol of NaCaEDTA or 1 nmol of DPA, drugs whose distribution is limited to the extracellular area. Injection of 10 ng zinc chloride i.t. had no long-term effect on nociception or on kainic acid-induced hyperalgesia. Whether zinc is translocated in response to a hyperalgesic dose of kainic acid was determined using the zinc-selective dye, N-(6-methoxy-8-quinolyl)-para-toluenensulfonamide (TSQ), which produces a delicate stain in the neuropil of the mouse spinal cord as well as a dense stain in the hippocampus. Injection of a hyperalgesic dose of kainic acid failed to alter TSQ fluorescence in either the spinal cord or hippocampus, in contrast to the distinct bleaching of TSQ in the hippocampus 24 h after a convulsant dose of kainic acid. Together these data suggest that, while not translocated, zinc in the extracellular area is necessary but not sufficient for the development of kainic acid-induced hyperalgesia.

Aminoquinolines↗
PubMed2000

Preinjury treatment with morphine or ketamine inhibits the development of experimentally induced secondary hyperalgesia in man.

We examine the effect of morphine or ketamine (N-methyl-D-aspartate receptor antagonist; NMDA) treatment on secondary hyperalgesia. Drug treatment started preinjury and continued into the early postinjury period. Hyperalgesia was induced by a local 1 degrees burn injury covering 12.5 cm(2) on the medial side of the calf. In this double-blind, cross-over study, 12 healthy volunteers received, on 3 separate days and in randomized order: (1) placebo; (2) morphine, bolus 150 microg/kg + infusion 1 microg/kg per min and 0.5 microg/kg per min; and (3) ketamine, bolus 60 microg/kg + infusion 6 microg/kg per min and 3 microg/kg per min. Bolus + infusion started 30 min before injury and ended 50 min after it. The area of secondary hyperalgesia was quantitated using punctate (von Frey filaments) and brush stimuli (electric brush). On the day of placebo, all subjects developed an area of hyperalgesia to punctate and brush stimuli outside the thermal injury (secondary hyperalgesia). We show that ketamine or morphine treatment starting preinjury significantly reduces this development (P<0.01, both). In a previous study, we found that postinjury treatment alone with morphine did not affect secondary hyperalgesia, whereas ketamine did so significantly. The differential response to morphine administered pre- or postinjury may be relevant to the recently shown NMDA receptor mediated interaction of central hyperexcitability and morphine antinociception. The effect of ketamine supports the hypothesis of the role of NMDA receptor mediation in central hyperexcitability.

Adult↗
PubMed2001

The effects of GABA(B) agonists and gabapentin on mechanical hyperalgesia in models of neuropathic and inflammatory pain in the rat.

We have examined the effects of a novel GABA(B) agonist, CGP35024, in models of chronic neuropathic (partial sciatic ligation) and inflammatory (Freund's complete adjuvant) pain in the rat, and its inhibitory action on spinal transmission in vitro. The effects of CGP35024 were compared with L-baclofen and gabapentin. CGP35024 and L-baclofen reversed neuropathic mechanical hyperalgesia following single subcutaneous or intrathecal administration, but did not affect inflammatory mechanical hyperalgesia. Gabapentin only moderately affected neuropathic hyperalgesia following a single administration by either route, but produced significant reversal following daily administration for 5 days. It was only weakly active against inflammatory hyperalgesia following single or repeated administration. The antihyperalgesic effects of L-baclofen and CGP35024, but not gabapentin, were blocked by the selective GABA(B) receptor antagonist CGP56433A. CGP35024 was seven times more potent against neuropathic hyperalgesia than in the rotarod test for motor co-ordination, whilst L-baclofen was approximately equipotent in the two tests. In the isolated hemisected spinal cord from the rat, CGP35024, L-baclofen and gabapentin all inhibited capsaicin-evoked ventral root potentials (VRPs). CGP35024 and L-baclofen, but not gabapentin, also inhibited the polysynaptic and monosynaptic phases of electrically-evoked VRPs, as well as the 'wind-up' response to repetitive stimulation. These data indicate that CGP35024 and L-baclofen modulate nociceptive transmission in the spinal cord to inhibit neuropathic hyperalgesia, and that CGP35024 has a therapeutic window for antihyperalgesia over spasmolysis.

Acetates↗
PubMed2002

Influence of endometriosis on pain behaviors and muscle hyperalgesia induced by a ureteral calculosis in female rats.

Endometriosis and urinary calculosis can co-occur. Clinical studies have shown that both painful and non-painful endometriosis in women are associated with enhanced pain and referred muscle hyperalgesia from urinary calculosis, but the mechanisms underlying this phenomenon are still poorly understood. The aim of this study was to develop an animal model adequate to explore this viscero-visceral interaction in standardized conditions. Using a model of endometriosis previously developed to study reduced fertility and vaginal hyperalgesia, endometriosis (endo) or sham-endometriosis (sham-endo) was induced in rats by autotransplantation of small pieces of uterus (or, for sham-endo, fat) on cascade mesenteric arteries, ovary, and abdominal wall. After the endometrial, but not the fat autografts had produced fluid-filled cysts (3 weeks), urinary calculosis was induced by implanting an artificial stone into one ureter. Pain behaviors were monitored by continuous 24-h videotape recordings before and after stone implantation. Referred muscle hyperalgesia was assessed by measuring vocalization thresholds to electrical stimulation of the oblique musculature (L1 dermatome). The data were compared with previously reported data from rats that had received only the stone. Neither endo nor sham-endo alone induced pain behaviors. Following stone implantation, in endo rats compared to sham-endo and stone-only rats, pain behaviors specifically associated with urinary calculosis were significantly increased and new pain behaviors specifically associated with uterine pathology became evident. Muscle hyperalgesia was also significantly increased. To explore the relationship between the amount of endometriosis and that of ureteral pain behavior, two separate groups of endo rats were treated with either a standard non-steroidal anti-inflammatory drugs (ketoprofen) or placebo from the 12th to the 18th day after endometriosis induction. The stone was implanted on the 21st day. Ketoprofen treatment compared to placebo significantly reduced the size of the cysts and both ureteral and uterine pain behaviors post-stone implantation. The size of the cysts showed a significant linear correlation with the post-stone ureteral pain behaviors. In conclusion, endo increased pain crises and muscle hyperalgesia typically induced by a ureteral calculosis, and the ureteral calculosis revealed additional pain behaviors typically induced by uterine pathophysiology; and this enhancement was a function of the degree of endometriosis. This result closely reproduces the condition observed in humans and could be due to a phenomenon of 'viscero-visceral' hyperalgesia, in which increased input from the cyst implantation sites to common spinal cord segments (T10-L1) facilitates the central effect of input from the urinary tract.

Abdominal Muscles↗
PubMed2003

Cold allodynia and hyperalgesia in neuropathic pain: the effect of N-methyl-D-aspartate (NMDA) receptor antagonist ketamine--a double-blind, cross-over comparison with alfentanil and placebo.

Cold allodynia and hyperalgesia are frequent clinical findings in patients with neuropathic pain. While there have been several clinical studies showing the involvement of central sensitization mechanisms and N-methyl-D-aspartate (NMDA) receptor activation in mechanical allodynia/hyperalgesia and ongoing pain, the mechanisms of thermal allodynia and hyperalgesia have received less attention. The aim of the present study was to examine the effect of the NMDA-receptor antagonist ketamine on thermal allodynia/hyperalgesia, ongoing pain and mechanical allodynia/hyperalgesia in patients with neuropathic pain (11 patients with post-traumatic neuralgia and one patient with post-herpetic neuralgia). All the patients were known to suffer from severe cold allodynia (cold pain detection threshold (CPDT): 23.8 degrees C, median value). The mu-opioid agonist alfentanil was used as an active control. The study design was double-blind and placebo-controlled and the drugs were administered i.v. (bolus dose and infusion). CPDT in the asymptomatic contralateral area was found to be significantly decreased (cold allodynia) compared to CPDT in site- and age-matched normal controls. Heat pain detection thresholds were found to be normal and no consistent heat hyperalgesia occurred. Alfentanil significantly reduced cold allodynia (by increasing CPDT) in symptomatic area (P=0.0076). Ketamine did not significantly increase the threshold. Significant and marked reductions of hyperalgesia to cold (visual analogue score at threshold value) were seen following both alfentanil (4.5 before, 1.4 after, median value) and ketamine (6.8 before, 0.4 after, median value). Alfentanil and ketamine also significantly reduced ongoing pain and mechanical hyperalgesia. It is concluded that NMDA-receptor mediated central sensitization is involved in cold hyperalgesia, but since CPDT remained unaltered, it is likely that other mechanisms are present.

Adult↗
PubMed1996

Venlafaxine hydrochloride (Effexor) relieves thermal hyperalgesia in rats with an experimental mononeuropathy.

Venlafaxine hydrochloride (Effexor) is a structurally novel antidepressant that inhibits reuptake of 5-hydroxytryptamine and noradrenaline, but unlike the older antidepressants, has few side-effects. The objective of this study was to determine whether venlafaxine relieves thermal hyperalgesia in rats with neuropathic pain due to chronic constriction injury (CCI) of the sciatic nerve. Paw withdrawal latency (PWL) to heat was tested for each hind paw. A painful neuropathy was induced in 24 male Sprague-Dawley rats (Group 1) as described by Bennett and Xie. Rats randomly received either oral venlafaxine (22 mg/kg) or placebo via gavage feeding beginning the day after surgery. Postoperative PWL testing began 3 days after CCI (Time 0). A second group of 12 rats (Group 2) was used to confirm that venlafaxine reverses hyperalgesia in rats with a fully developed neuropathic lesion. These animals began to receive oral venlafaxine (22 mg/kg) starting on the third postoperative day, after the presence of thermal hyperalgesia was verified through PWL testing. Testing was continued for 5 days, during venlafaxine administration. A third group of 12 rats (Group 3) had activity measured before and after treatment with venlafaxine (22 mg/kg). Rats in the placebo group developed thermal hyperalgesia while those that received venlafaxine did not. Venlafaxine also appeared to have a mild non-specific analgesic effect that increased PWL in the sham limb. In Group 2, thermal hyperalgesia was present on day 3, but following treatment with venlafaxine, thermal hyperalgesia resolved. Activity measurements confirmed that venlafaxine was not sedating in this rat model.

Administration, Oral↗
PubMed1997

Blockade of calcium channels can prevent the onset of secondary hyperalgesia and allodynia induced by intradermal injection of capsaicin in rats.

Intradermal capsaicin injection in humans results in primary hyperalgesia to heat and mechanical stimuli applied near the injection site, as well as secondary mechanical hyperalgesia (increased pain from noxious stimuli) and mechanical allodynia (pain from innocuous stimuli) in an area surrounding the site of primary hyperalgesia. This study in rats tested the hypothesis that the secondary hyperalgesia and allodynia observed following intradermal injection of capsaicin was dependent upon activation of voltage sensitive calcium channels in the spinal cord. Responses to application of von Frey filaments of 10 mN and 90 mN bending forces were tested in all rats before and after injection of capsaicin into the plantar surface of a hindpaw. Animals were pretreated with L-type (nifedipine), N-type (omega-conotoxin GVIA) or P-type (omega-agatoxin IVA) calcium channels blockers through a microdialysis fiber implanted in the spinal dorsal horn prior to the injection of capsaicin. None of the calcium channel blockers had any affect on normal sensory or motor responses. However, all three blockers dose dependently prevented the development of secondary mechanical hyperalgesia and allodynia. The threshold to mechanical stimulation with von Frey filaments was also increased significantly in animals treated with these calcium channel blockers when compared to articial cerebrospinal fluid control animals. These data suggest that calcium channels are important for the development of mechanical hyperalgesia and allodynia that occurs following capsaicin injection.

Animals↗
PubMed1998

A pharmacologic analysis of mechanical hyperalgesia in streptozotocin/diabetic rats.

This study used streptozotocin (STZ; 50 mg/kg i.p.) diabetic rats and monitored weekly thermal and mechanical nociceptive thresholds for 8 weeks diabetes. Rats developed mechanical hyperalgesia as soon as 2 weeks after STZ injection. Thermal nociceptive threshold was not altered up to 8 weeks after STZ injection. Four week-diabetic rat mechanical hyperalgesia showed reduced sensitivity to the antinociceptive effect of morphine (5-20 mg/kg i.p.). Furthermore, a reduced sensitivity to the antinociceptive effect of the GABA(B) agonist, (+/-)baclofen, was observed. A dose as high as 16 mg/kg i.p. of (+/-)baclofen was necessary to reverse 4 week-diabetic rat hyperalgesia, whereas in control rats the highest antinociceptive dose devoid of muscle-relaxant effect was 4 mg/kg i.p. The non-peptide antagonist for the substance P, neurokinin, (NK1) receptor, RP 67580 (3-9 mg/kg i.p.) was not effective in reversing the mechanical hyperalgesia associated with 4 week-diabetes. A six day-treatment with an antagonist for the N-methyl-D-aspartate (NMDA) receptor for glutamate, (+)MK-801 (0.1 mg/kg i.p. twice a day), gradually but completely reversed 4 week-diabetes-induced mechanical hyperalgesia. These data suggest that diabetes-induced hyperalgesia may be the consequence of increased activity of primary afferent fibres leading to an increased excitatory tone within the spinal cord. An increased release of glutamate and activation of the NMDA receptor, would maintain the hyperalgesic state. Reduced activity of both opioidergic and GABA(B)ergic inhibitory systems, might exacerbate the increased excitation thus contributing to the ongoing pain. It is suggested that NMDA receptor antagonists may constitute an alternative therapy for diabetic neuropathic pain.

Animals↗
PubMed1998

Treatment with either high or low frequency TENS reduces the secondary hyperalgesia observed after injection of kaolin and carrageenan into the knee joint.

For years, physical therapists have been utilizing a variety of modalities, including transcutaneous electrical nerve stimulation (TENS), in an attempt to manage pain associated with inflammation. However, the data on clinical effectiveness is conflicting and the neurophysiological mechanism of action is not known. The purpose of this study was to investigate the effects of high and low frequency TENS on the secondary hyperalgesia that occurs after joint inflammation. Secondary hyperalgesia is thought to reflect changes in central neurons and is thus a measure of activity of central neurons. This study utilized the kaolin and carrageenan model of knee joint inflammation and measured the effects of TENS treatment on paw withdrawal latency to radiant heat (secondary hyperalgesia), spontaneous pain behaviors and joint circumference. Either high (100 Hz) or low (4 Hz) frequency TENS was applied to the knee joint for 20 min after the development of hyperalgesia. Both high and low frequency TENS resulted in a reversal of the hyperalgesia immediately following treatment. The effects of high frequency TENS lasted through at least 24 h while those of low frequency TENS lasted through 12 h. There was no effect of TENS on spontaneous pain behaviors or joint swelling when compared to controls. Thus, TENS appears to be more effective in reducing referred pain (or secondary hyperalgesia) without affecting guarding or splinting of the affected limb. Thus, clinically, the choice to use TENS may depend on patient symptoms; specifically TENS should be effective in reducing referred or radiating pain.

Animals↗
PubMed1999

Patterns of hyperalgesia in complex regional pain syndrome.

Complex regional pain syndrome (CRPS) is characterized by a triad of sensory, motor and autonomic dysfunctions, with long-standing pain and temperature differences of the affected and contralateral limb as predominant symptoms. The pathogenesis of the disorder still remains unclear. Among the main hypotheses of an underlying pathophysiology we find inflammatory processes and dysfunction of the sympathetic nervous system. Whether the main site of dysfunction is found centrally or peripherally is not known. With psychophysical methods we studied patterns of hyperalgesia to obtain a better understanding of the neuropathic pain component in CRPS. Forty patients in an acute phase of CRPS and a median duration of the disease of 10 weeks, were included in the study. Hyperalgesia to heat was tested with a thermode providing feedback-controlled temperature increases. Two forms of mechanical hyperalgesia were examined: phasic mechanical stimuli by using a custom-made impact stimulator for the determination of individual pain thresholds, tonic mechanical stimuli were applied using a pinch-device. Additionally a 'wind-up' paradigm was used to study a pain phenomenon of presumed central origin: a defined impact stimulus was given once and five times in repetition. A subpopulation of patients was reevaluated for mechanical hyperalgesia after i.v. injection of 500 mg acetyl-salicylic acid. Hyperalgesia to heat was insignificant. We found, however, a marked mechanical hyperalgesia to phasic impact stimuli (P < 0.005), whereas, static stimulation (squeezing skin folds) results were insignificant again. Wind-up related pain was also significantly enhanced in the affected limb (P < 0.02). The anti-inflammatory agent had no effect. These results indicate a non-inflammatory pathogenesis in CRPS presumably central in origin.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1999

Spinal neurokinin3 receptors mediate thermal but not mechanical hyperalgesia via nitric oxide.

Although intrathecally administered senktide, an agonist at the neurokinin3 receptor, attenuates withdrawal responses to noxious stimuli in the restrained animal, senktide increases motor neuron activity in spinal cords of neonatal rats and facilitates the electrically-evoked nociceptive flexor reflex in the adult rat. The present study examined the effects of intrathecal administration of senktide on withdrawal responses to noxious thermal and mechanical stimuli in awake, unrestrained, adult rats. Intrathecal administration of senktide (10 nmol) in chronically catheterized rats did not alter the responses elicited by a noxious mechanical stimulus (508 mN, von Frey monofilament). Conversely, intrathecal senktide (10 nmol) induced thermal hyperalgesia, indicated by decreased withdrawal latency to radiant heat. Thermal hyperalgesia peaked 20-26 min following drug injection and returned to normal within 30 min. SR 142801 (60 nmol), a non-peptide neurokinin3 receptor antagonist, inhibited the senktide-induced hyperalgesia, providing further support that the effect of senktide is mediated by neurokinin3 receptors. Pretreatment with N(G)-nitro-L-arginine methyl ester (30 nmol), a nitric oxide synthase inhibitor, blocked the effect of senktide, indicating that senktide-induced thermal hyperalgesia is also mediated by the production of nitric oxide. Intrathecal senktide produced vasodilation and increased skin temperature in the hind paw. Intravenous hexamethonium, a ganglionic nicotinic receptor antagonist, similarly increased paw temperature without decreasing withdrawal latency to radiant heat. Thus, the increased skin temperature associated with intrathecal senktide was insufficient to account for the thermal hyperalgesia observed. Collectively, the present work demonstrates that NK3 receptors mediate thermal but not mechanical hyperalgesia through a pathway that involves the production of NO.

Animals↗
PubMed1999

Parenterally administered kainic acid induces a persistent hyperalgesia in the mouse and rat.

Nociceptive primary afferent C-fibers express a subset of glutamate receptors that are sensitive to kainic acid. Thus, we tested the possibility that activation of these receptors alters nociception. Intraperitoneal (i.p.) injection of kainic acid induced a persistent thermal hyperalgesia, when tested using the hot plate (mice) and tail flick (mice and rats) assays, and mechanical hyperalgesia when tested using von Frey monofilaments (rats), but had no effect on acetic acid-induced chemical nociception (mice). When administered i. p., 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), an (R, S)-alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid HBr/kainate (AMPA/KA) antagonist, completely blocked hyperalgesia. When injected intrathecally (i.t.), kainic acid itself failed to induce hyperalgesia and AMPA/KA antagonists given i.t. also failed to attenuate the hyperalgesic effect of kainic acid administered i.p. , indicating that the spinal cord is not the primary site of action. Kainic acid injected subcutaneously in the back of mice decreased response latencies in the hot plate and tail flick assays, indicating that hyperalgesia is achieved by a variety of parenteral routes of injection. Histological evaluation of rat spinal cord and dorsal root ganglia revealed no neurodegenerative changes 24 h after kainic acid. Together these data suggest that a persistent hyperalgesia results from the transient activation of AMPA/KA receptors that are located outside the spinal cord, perhaps on the distal projections of primary afferent fibers.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed2000

Deficits in visceral pain and hyperalgesia of mice with a disruption of the tachykinin NK1 receptor gene.

Studies in mice lacking genes encoding for substance P or its receptor (NK1), or with NK1 antagonists, have shown that this system contributes to nociception, but the data are complex. Here, we have further examined the role of NK1 receptors in pain and hyperalgesia by comparing nociceptive responses to mechanical and chemical stimulation of viscera and the resulting hyperalgesia and inflammation in NK1 knockout (-/-) and wild-type (+/+) mice. We concentrated on visceral nociception because substance P is expressed by a much greater proportion of visceral than cutaneous afferents. NK1 -/- mice showed normal responses to visceral mechanical stimuli, measured as behavioural responses to intraperitoneal acetylcholine or hypertonic saline or reflex responses to colon distension in anaesthetized mice, although -/- mice failed to encode the intensity of noxious colon distensions. In contrast, NK1 -/- mice showed profound deficits in spontaneous behavioural reactions to an acute visceral chemical stimulus (intracolonic capsaicin) and failed to develop referred hyperalgesia or tissue oedema. However, in an identical procedure, intracolonic mustard oil evoked normal spontaneous behaviour, referred hyperalgesia and oedema in -/- mice. The inflammatory effects of capsaicin were abolished by denervation of the extrinsic innervation of the colon in rats, whereas those of mustard oil were unchanged, showing that intracolonic capsaicin evokes neurogenic inflammation, but mustard oil does not. Tests of other neurogenic inflammatory stimuli in NK1 -/- mice revealed impaired behavioural responses to cyclophosphamide cystitis and no acute reflex responses or primary hyperalgesia to intracolonic acetic acid. We conclude that NK1 receptors have an essential role mediating central nociceptive and peripheral inflammatory responses to noxious stimuli that evoke neurogenic inflammation, and modulating responses to noxious mechanical stimuli. We propose that two separate hyperalgesia pathways exist, one of which is NK1 receptor dependent, whereas the other does not require intact substance P/NK1 signalling.

Acetic Acid↗
PubMed2001

Hyperalgesia induced by peripheral inflammation is mediated by protein kinase C betaII isozyme in the rat spinal cord.

We have addressed the molecular mechanism(s) of hyperalgesia, which depends on increased excitability of dorsal horn neurons and on sensitization of primary afferent nociceptors, during peripheral inflammation. Following unilateral adjuvant-induced inflammation in the rat hind paw, time-course changes in behavioral hyperalgesia and functional activities of Ca2+/phospholipid-dependent protein kinase C isozymes were examined. Inflammation was characterized by increase in paw diameter, and behavioral hyperalgesia was quantified as paw withdrawal latency from a radiant heat source. Behavioral hyperalgesia on the injected paw was significantly increased. This was accompanied by a significant increase in total functional membrane-associated protein kinase C activity, whereas total cytosolic protein kinase C activity was unchanged on the sides of the lumbar spinal cord both contralateral and ipsilateral to the inflammation. Importantly, on the side of lumbar cord ipsilateral to the inflamed paw, the activity of membrane-associated protein kinase CbetaII was increased following the same time-course as the paw withdrawal latency decrease, suggesting an increased translocation of protein kinase Cbetall to the membrane related to behavioral hyperalgesia. A defined mixture of purified gangliosides, which inhibits intracellular protein kinase C translocation and activation, decreased inflammation-induced paw withdrawal latency, and specifically decreased the activity of membrane-associated protein kinase Cbetall on the side of the spinal cord ipsilateral to the inflammation. Quantitative immunohistochemical analyses demonstrated intensified protein kinase CbetaII-like immunoreactivity on the side of the spinal cord ipsilateral to the inflammation. Time-course for increases in the activity of membrane-associated protein kinase CbetaII, and in intensity of protein kinase CbetaII-immunoreactivity, paralleled inflammation-mediated changes in paw withdrawal latency and paw diameter. Our findings indicate an apparent involvement of protein kinase CbetaII isozyme specifically in the molecular mechanism(s) of thermal hyperalgesia.

Animals↗
PubMed1999

Intrathecal substance P-induced thermal hyperalgesia and spinal release of prostaglandin E2 and amino acids.

Substance P is an important neuromediator in spinal synaptic transmission, particularly in processing nociceptive afferent information. The effects of substance P are mediated by activation of the neurokinin 1 receptor. Evidence has suggested that excitatory amino acids such as glutamate, and prostaglandins including prostaglandin E2 are involved in the enhanced spinal excitability and hyperalgesia produced by spinal substance P. In the present study, we have demonstrated that intrathecal injection of substance P (20 nmol) in rats chronically implanted with intrathecal dialysis catheters induced a decrease in thermal paw withdrawal latency (before: 10.4+/-0.3 s; after 7.6+/-0.6 s), which was accompanied by an increase in prostaglandin E2 (362+/-37% of baseline), glutamate (267+/-84%) and taurine (279+/-57%), but not glycine, glutamine, serine or asparagine. Intrathecal injection of artificial cerebrospinal fluid had no effect upon the behavior or release. Substance P-induced thermal hyperalgesia and prostaglandin E2 release were significantly attenuated by a selective neurokinin 1 receptor antagonist RP67580, but not by an enantiomer RP68651. However, substance P-induced release of glutamate and taurine was not reduced by treatment with RP67580. SR140333, another neurokinin 1 receptor antagonist, displayed the same effects as RP67580 (i.e. block of thermal hyperalgesia and prostaglandin E2 release, but not release of amino acids). These results provide direct evidence suggesting that the spinal substance P-induced thermal hyperalgesia is mediated by an increase in spinal prostaglandin E2 via activation of the neurokinin 1 receptor. These findings define an important linkage between small afferents, sensory neurotransmitter release and spinal prostanoids in the cascade of spinally-mediated hyperalgesia. The evoked release of glutamate is apparently not a result of activation of neurokinin 1 receptors. Accordingly, consistent with other pharmacological data, acute spinal glutamate release does not contribute to the hyperalgesia induced by activation of spinal neurokinin 1 receptors.

Amino Acids↗
PubMed1999

Hyperalgesia due to nerve injury: role of prostaglandins.

The hypothesis that prostaglandins contribute to hyperalgesia resulting from nerve injury was tested in rats in which the sciatic nerve was partially transected on one side. Subcutaneous injection of indomethacin (a classic inhibitor of cyclo-oxygenase) into the affected hindpaw relieved mechanical hyperalgesia for up to 10 days after injection. Subcutaneous injection of meloxicam or SC-58125 (selective inhibitors of cyclo-oxygenase-2) into the affected hindpaw also relieved mechanical hyperalgesia, but with a shorter time-course. Subcutaneous injection of SC-19220 (an EP1 prostaglandin receptor blocker) into the affected hindpaw produced significant relief of mechanical and thermal hyperalgesia. Comparable injections into the contralateral paw or abdomen had no effect on mechanical or thermal hyperalgesia, suggesting that the effects we observed were local rather than systemic. We conclude that prostaglandins, probably prostaglandin E1 or E2, contribute to the peripheral mechanisms underlying hyperalgesia following nerve injury. These data provide further evidence that inflammatory mediators contribute to neuropathic pain, and may warrant further study of peripherally administered non-steroidal anti-inflammatory drugs as a possible treatment for such pain in patients.

Animals↗
PubMed2002

Indomethacin, caffeine and prochlorperazine alone and combined revert hyperalgesia in in vivo models of migraine.

The combination of indomethacin, caffeine, and prochlorperazine (hereinafter IndoProCaf) represents an effective antimigraine drug available on the Italian market. The aim of this study was to test the efficacy of the three active principles alone and in combination in reverting hyperalgesia. Hyperalgesia was induced by morphine withdrawal in mice treated with morphine for 15 days and then made hyperalgic by morphine substitution with water. This study showed that indomethacin 0.3 mg kg(-1), i.p.; caffeine 0.1 and 0.3 mg kg(-1), i.p.; and prochlorperazine 0.1 mg kg(-1), i.p.; as well as the combination of the three active principles, were able to revert morphine withdrawal induced hyperalgesia, causing a statistically significant increase of pain threshold in hyperalgic mice. In a second model, hyperalgesia was induced by the i.p. injection of a 0.3% solution of acetic acid in mice and was evaluated counting the number of abdominal constrictions. Indomethacin (0.1 mg kg(-1), i.p.), caffeine (0.3 mg kg(-1), i.p.), and prochlorperazine (0.1 mg kg(-1), i.p.) reduced the number of abdominal constrictions, while the combination of the three active principles was able to abolish almost completely the abdominal constrictions, with a significantly higher efficacy compared to the single active principles. In both models, indomethacin, caffeine, and prochlorperazine reverted hyperalgesia at dosages 10 times lower than the corresponding analgesic ones. These data provide the pharmacologic evidence of the efficacy of IndoProCaf in reverting hyperalgesia, a condition of reduction of pain threshold similar to that occurring in migraine.

Acetic Acid↗