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Objective: We employed the 'delayed onset of muscle soreness' (DOMS) and the 'hypertonic saline' muscle pain models in combination with muscle microdialysis to evaluate the role of potentially algesic substances (lactate, glutamate, prostaglandin E2 (PGE2), nitric oxide (NO) and substance P (SP)) in the development of human muscle pain., Methods: DOMS was induced by 2 sets of 50 concentric/eccentric contractions of the calf muscles 24 h before the start of microdialysis. During microdialysis pain was stimulated through calf muscle contractions (dorsal and plantar flexions of the foot). Hypertonic saline was injected into the biceps muscle (5 x 200 microl 5.8% NaCl, 2 min interval) during dialysis. The calf (no treatment) and biceps (normal saline) of the other side was used as control., Results: Both models reliably induced muscle pain with similar intensities as assessed by visual analog scale. The DOMS exercise caused an increase of lactate in serum and the calf muscles of the DOMS leg. In addition, glutamate, PGE2 and substance P dialysate concentrations increased following contraction-induced pain stimulation (peak concentrations 125 +/- 20 microM, 239 +/- 45 pg/ml and 60 +/- 11 pg/ml for glutamate, PGE2 and SP, respectively). This increase did not occur in the control leg (peak concentrations 97 +/- 12 microM, 114 +/- 26 pg/ml and 46 +/- 9 pg/ml for glutamate, PGE2 and SP, respectively). Concentrations of nitric oxide were lower in the DOMS than control leg, particularly during the first 4h of microdialysis. Injection of hypertonic saline into the biceps muscle caused a significant increase of dialysate glutamate concentrations (peak 50 +/- 3 microM) whereas glutamate remained constant after injection of normal saline (mean 26 +/- 1 microM). Injection of hypertonic saline had no effect on lactate, PGE2 or NO levels., Conclusion: Our data support the notion that an inflammatory reaction may be involved in muscle soreness following eccentric exercise, whereas the injection of hypertonic saline into the muscle probably directly stimulates muscle nociceptors and causes glutamate release.

Topical analgesics are widely marketed for treatment of muscle and joint pain. We have recently developed a model of muscle pain and have used this model to evaluate the efficacy of commercially available topical and peroral ketoprofen in order to evaluate the time- and dose-dependence of analgesia. In the present study, we examined the dose- (0, 50, and 100 mg) and time-dependence (hourly to 8 h) of commercially available peroral and topical ketoprofen. In order to achieve infusion times of 8 h (and thus study the time course of analgesic action), we adapted the model of low pH-induced muscle pain in humans to these requirements by applying the infusions continuously for 10 min every hour for 8 h. We found that the 10 min infusion produced reliable and consistent pain levels that were reproducible over the 8 h of the study. The study was performed double-blind, randomized, and with a 1-week interval between each of five different sessions (cross-over). Altogether six volunteers underwent intramuscular infusions of isotonic phosphate-buffered saline solution of pH 5.2; during each 8 h session the infusion was switched on eight times with a duration of 10 min at 50 min intervals (there was no infusion during the 50 min interval). The intramuscular infusion of low pH phosphate buffer induced a localized dull-aching or stinging muscle pain sensation; the flow rate of the pH infusion was individually adjusted to induce pain of a magnitude of 20% on a visual analogue scale (ranging from "no pain" (0%) to "unbearable pain" (100%)). Twenty minutes after starting the infusion the volunteers received a capsule with either a placebo or 50 or 100 mg ketoprofen perorally and, in addition, either placebo gel or 50 or 100 mg of a 2.5% commercial ketoprofen gel was applied topically to the skin. One of the sessions included a placebo gel and an oral placebo. The intensity of the recurrent pain stimulus was significantly reduced by 59% following administration of 100 mg peroral ketoprofen within the first 3 h (P<0.03, Wilcoxon test); this analgesia lasted up to the sixth hour of the experimental protocol. Oral ketoprofen (50 mg) was less effective and reduced the pain intensity by 45% (P<0.05) from only the second to the third hour. In contrast, pain reduction after topical ketoprofen application was not of the same magnitude but appeared to be faster to develop (with a maximum effect within 1 h) on average. The maximum pain suppression with 100 mg topical 2.5% ketoprofen gel was by 51% (significant with P<0.03), while 50 mg topical ketoprofen produced a non-significant reduction of 29%. The apparent analgesia was rapid to develop but transient and pain ratings increased back to baseline values within 3 h for the 100 mg dose and within 2 h for the 50 mg dose. This data suggests that topical application of commercial gel-based systems does not provide long-lasting analgesia in the muscle when compared to perorally-dosed ketoprofen. In addition, the data show that even doses of 100 mg peroral ketoprofen do not provide complete relief of muscle pain.

Study Design: This study was designed to evaluate whether allografts of intervertebral disc materials produce hyperalgesia in the rat and whether an immune response, pH, or chemicals correlate with the induced hyperalgesia., Objective: To elucidate the pathomechanisms of radicular pain secondary to lumbar disc herniation., Summary of Background Data: It has been reported that a low pH, an autoimmune reaction, or chemical radiculitis is likely responsible for radicular pain associated with lumbar disc herniation. In animal studies, it has been shown that hyperalgesia (an increased sensitivity to painful stimuli) involves activation of phospholipase A2 and nitric oxide synthase., Methods: Fat, nucleus pulposus, and anulus fibrosus were allografted into the epidural space at L6 in the rat. Withdrawal response thresholds to mechanical stimuli and withdrawal response latencies to thermal stimuli on the tail and pH in the applied tissues were measured after surgery. Interleukin-1, phospholipase A2, and nitric oxide synthase were examined in the applied tissues using immunohistochemistry, nicotineamide adenine dinucleotide phosphate-diaphorase histochemistry, and in situ hybridization., Results: Allografted fat did not produce hyperalgesia. Allografts of nucleus pulposus and nucleus pulposus plus anulus fibrosis showed evidence of mechanical and thermal hyperalgesia, respectively. There were no observed changes in pH over time. Although interleukin-1 was demonstrated in all applied tissues, phospholipase A2 was only observed around the applied nucleus A2 was only observed around the applied nucleus pulposus and nucleus pulposus plus anulus fibrosus. Nitric oxide synthase was only markedly increased around the applied tissues., Conclusion: The nucleus pulposus and anulus fibrosus produce different forms of hyperalgesia (mechanical vs. thermal) associated with different and distinct immunohistochemical changes. It is possible that radicular pain of a lumbar disc herniation results from chemicals, such as phospholipase A2 and nitric oxide.

Objective: A series of experiments were designed to develop and validate an animal model of lumbar radiculopathy. More specifically, these investigations introduced a model of chronic neuropathic pain in the rat associated with clinically relevant lumbar nerve root trauma and evaluated the ability of the model to effect symptoms and begin to understand the underlying neurochemical and neurophysiologic factors associated with these neurologic abnormalities., Summary of Background Data: A search of the literature suggested that these studies were a first attempt to distinguish and elucidate an experimental lumbar radiculopathy., Methods: Two basic approaches to nerve trauma were considered, direct damage to the nerve via compression, and introduction of foreign materials in proximity to the nerve root that might cause irritation and inflammation leading to chronic symptoms. Ligature around the nerve (i.e., surrounding the nerve with a suture) was considered a plausible irritant that might behave in an animal model in a similar way that nerve root entrapment, often observed in HNP and stenosis cases, might function in humans. Further, varying levels of irritation was modeled by using 4-0 silk as a mild and 4-0 chromic gut as a more harsh irritant., Study Design: Five distinct treatments of the nerve roots were investigated initially: 1) a sham intervention, where the surgery simply exposed the nerve roots and dorsal root ganglion followed by standard closing procedures; 2) nerve root clipping, where the nerve roots were clipped with a microhemoclip; 3) 4-0 silk ligature, where two loose ligatures of 4-0 silk were placed around the nerve roots; 4) 4-0 chromic gut 1, where one loose ligature of 4-0 chromic gut was placed around the nerve roots; and 5) 4-0 chromic gut 2, where four 0.3 cm pieces of 4-0 chromic gut were laid adjacent to the nerve roots and secured by two loose ligatures of 4-0 chromic gut. ANOVA techniques were used to test for differential effects across time for the five treatment groups in terms of animal function and biochemistry in the DRG., Results: Rats treated with chromic gut ligature in large quantity demonstrated differential patterns of results on the injured and noninjured sides consistent with a lumbar radiculopathy. The injured side demonstrated significantly worse thermal hyperalgesia related to neuropathic pain (P < 0.0001); initial mechanical hypoalgesia (P < .001), and motor dysfunction (P < .001) resolving within 2 weeks; significantly increased c-fos counts (P < .0001) 2 weeks postoperatively, which showed a consistent trend toward baseline and return to baseline by 12 weeks; significantly greater and highly increased VIP concentrations in the dorsal root ganglia 2 weeks postoperatively (P < .0001) that did not resolve or tend towards baseline after 12 weeks of follow-up in conjunction with a trend toward VIP depletion in the spinal cord 2 weeks postoperatively that did resolve to baseline until a 12-week concentration indicated a significant increase in concentration (P < .002). Quantitative and qualitative changes in c-fos and VIP, correlated with the patterns of behavior and function. Thus, for the first time, evidence to link outcome behaviors and function with underlying neurochemical processes is suggested., Conclusions: When the same apparent conditions can be demonstrated in some situations to be causing pain and in other situations to be independent of pain, some additional factor or factors not considered in the original investigations may be mediating the outcome. Neurochemical consequences of nerve root irritation provide a theoretical framework for hypothesizing about various types of mediating events that might explain how similar apparent pathology might reasonably lead to different predictions about behavior consequences of the pathology.(ABSTRACT TRUNCATED AT 400 WORDS)

Objective: The recently proposed animal model of lumbar radiculopathy was used to investigate behavioral consequences and histologic changes in spinal nerve roots, dorsal root ganglia, and spinal nerves after the L4, L5, and L6 nerve roots were loosely ligated with either silk or chromic gut sutures in an attempt to better understand the pathophysiologic mechanisms that give rise to pain associated with lumbar radiculopathy., Summary of Background Data: Little is known about the pathophysiologic mechanisms that give rise to pain associated with lumbar radiculopathy. The recently proposed animal model of unilateral lumbar radiculopathy, which demonstrated an association with motor paresis and thermal hyperalgesia of the affected hind limb and showed evidence of spontaneous pain has been demonstrated, may serve as a vehicle to allow direct investigation of the nature of the pathophysiological mechanisms associated with lumbar radiculopathy., Methods: Three distinct treatments of the nerve roots were initially investigated: 1) a sham intervention, where the surgery simply exposed the nerve roots and dorsal root ganglion followed by standard closing procedures; 2) 4-0 silk ligature, where two loose ligatures of 4-0 silk were placed around the nerve roots; and 3) 4-0 chromic gut 2, where four 0.3 cm pieces of 4-0 chromic gut were laid adjacent to the nerve roots and secured by two loose ligatures of 4-0 chromic gut., Study Design: ANOVA techniques were used to test for differential effects across time for the three treatment groups in terms of animal function. A qualitative analysis of the histology of the ipsilateral and contralateral nerve roots, dorsal root ganglia, and spinal nerves was done to correlate histologic changes with behavioral changes., Results: Behavioral results were consistent with the previous study. Rats treated with chromic gut, but not silk, reliably demonstrated a prolonged thermal hyperalgesia that was maximal 2 weeks after surgery and lasted for up to 12 weeks. These behavioral changes, however, were not correlated with histologic changes in myelinated fiber content in the L4, L5, and L6 nerve roots, dorsal root ganglia and spinal nerves, the ipsilateral spinal nerved, dorsal root ganglia, and nerve roots of rates ligated with silk or chromic gut showed similar, significant, decreased in the number of large diameter myelinated fibers., Conclusions: These results suggest that mechanical constriction of the L4, L5, and L6 spinal nerve roots, as evidenced by a loss of myelinated fibers, is not sufficient to produce the behavioral effects associated with this model of lumbar radiculopathy. It is hypothesized that chemical factors from the chromic gut play a role in the pathophysiology and development of the behavioral, but not histological, changes in this model of lumbar radiculopathy.

This report presents evidence that pericardial administration of a mixture of algogenic substances is a potentially useful model of cardiac nociception. In awake rats in which a looped silicone catheter had been placed in the pericardial sac at least 5 days previous, administration of a mixture containing equal concentrations of bradykinin (BK), acetylcholine (ACh), adenosine (ADEN), histamine (HIST), serotonin (5-HT) and prostaglandin E2 (PGE2) (total 25 nmol in 25 microliters) led to rapid acquisition of a passive avoidance behavior. In contrast, neither BK alone (5-25 nmol) nor the same mixture of ACh, ADEN, HIST, 5-HT and PGE2 without BK led to acquisition of the behavior or produced effects significantly different than produced by saline given into the pericardial sac in the same volume (25 microliters). Both BK and the mixture containing BK produced dose-dependent cardiovascular responses (pressor response and tachycardia) of similar magnitude. Neither saline nor the mixture without BK produced significant changes in mean arterial blood pressure or heart rate. In electrophysiological experiments in the same rats, thoracic spinal cord neurons responded dose-dependently to the mixture and, except for one neuron, responded also to BK in a dose-dependent manner. However, responses to BK, when compared to a similar dosage of BK contained in the mixture, were significantly less in magnitude and duration. All units received convergent somatic input from the thorax and all neurons also received convergent input from the esophagus. Balloon distension of the esophagus excited all units. Results of the behavioral characterization of algogenic substances administered into the pericardial sac of awake rats gave evidence of differences between the effects of BK and a mixture of six substances, including BK. BK in either of two dosages tested produced effects not different than saline while the mixture containing BK was aversive. In complementary electrophysiological studies, both BK and the mixture containing BK excited thoracic spinal cord neurons, suggesting that neuron responses to putative algogenic substances are not necessarily reliable measures of cardiac nociception.

Background: Combinations of opioids and nonsteroidal antiinflammatory drugs (NSAIDs) are commonly used to control pain in the perioperative period, yet there are no quantitative evaluations of the interaction between opioids and nonsteroidal antiinflammatory drugs during visceral nociception. This study evaluated the interaction between morphine and ketorolac during visceral nociception in the rat., Methods: The pressor response to noxious colorectal distention (80 mmHg, 20 s) was evaluated in 29 male Sprague-Dawley rats and dose-response curves were determined for intravenous morphine, ketorolac and the mixture of morphine and ketorolac. The data were interpreted using an isobolographic analysis to establish the nature of the interaction., Results: Intravenous ketorolac alone (8-32 mg/kg) did not have a significant antinociceptive effect, whereas morphine alone (1-4 mg/kg) produced significant antinociception during noxious colorectal distention (dose yielding a 50% reduction in nociceptive response relative to baseline pressor response = 1.7 +/- 0.6 mg/kg). Isobolographic analysis of the antinociceptive interaction demonstrated a highly significant, naloxone-reversible potentiation of intravenous morphine by ketorolac in the rat during visceral nociception (P < 0.001)., Conclusions: Ketorolac is a powerful potentiator of morphine antinociception during visceral nociception in the rat. However, intravenous ketorolac alone did not demonstrate antinociceptive properties during colorectal distention, a model of acute visceral nociception without a major inflammatory component. These data suggest that ketorolac may have a central modulatory effect on opioid pharmacology and the synergistic effect may be separate from its peripheral antiinflammatory properties. This study encourages further basic as well as clinical evaluations of the improved antinociception provided by combination therapy of opioids and nonsteroidal antiinflammatory drugs.

The effects of N-methyl-D-aspartate (100 amol-1 nmol) on the nociceptive tail-flick reflex were studied in awake rats. Lesser doses of N-methyl-D-aspartate (100 amol-10 pmol) administered intrathecally to the lumbar spinal cord produced a dose-dependent facilitation of the tail-flick reflex (maximum at 0.5-1 min). The greatest dose tested (1 nmol) inhibited the tail-flick reflex (maximum at 2-5 min) and produced a caudally directed scratching and biting behavior accompanied by vocalizations. Intrathecal pretreatment with the N-methyl-D-aspartate receptor antagonist, D-2-amino-5-phosphonovaleric acid (1 fmol-1 pmol), which produced no change in baseline tail-flick latency, blocked all N-methyl-D-aspartate produced effects in a dose-dependent manner (100 fmol D-2-amino-5-phosphonovaleric acid produced maximum blockage for about 40 min). The magnitude and duration of N-methyl-D-aspartate-produced biphasic effects on tail-flick latency were similar in awake and lightly pentobarbital-anesthetized rats, but caudally directed biting and scratching behavior was not produced in lightly anesthetized rats. Reversible spinalization at T8-T10 in lightly anesthetized rats (produced by cold-block) completely abolished inhibition of the tail-flick reflex produced by 1 nmol N-methyl-D-aspartate whereas facilitation produced by 10 pmol N-methyl-D-aspartate remained unchanged, indicating that N-methyl-D-aspartate-produced facilitation is a local, segmental effect and that N-methyl-D-aspartate-produced inhibition requires a supraspinal loop. To examine the nature of the supraspinal loop, potential contributions of descending noradrenergic and serotonergic systems were studied. Intrathecal pretreatment with 100 nmol phentolamine completely blocked N-methyl-D-aspartate-produced inhibition of the tail-flick reflex, while N-methyl-D-aspartate-produced facilitation and caudally directed biting and scratching behavior remained unchanged. Intrathecal pretreatment with 50 nmol methysergide reversed the inhibitory effect of 1 nmol N-methyl-D-aspartate, resulting in a potent and prolonged facilitation which could be blocked by D-2-amino-5-phosphonovaleric acid. (1 pmol). Intrathecal pretreatment with an alternate substrate for nitric oxide synthase, NG-nitro-L-arginine methyl ester (100 nmol), completely blocked N-methyl-D-aspartate-produced facilitation of the tail-flick reflex, whereas N-methyl-D-aspartate-produced inhibition and caudally directed biting and scratching behavior were unaffected.(ABSTRACT TRUNCATED AT 400 WORDS)

Recently, it has been reported that loosely constrictive chromic gut ligatures around the sciatic nerve produce behavioral evidence of neuropathic pain in rats. It has been shown that axonal swelling after ligation results in a constriction injury associated with a decrease in the number of both large-diameter myelinated and small-diameter unmyelinated axons, but the mechanism(s) producing spontaneous pain and thermal hyperalgesia remain largely unknown. The present study systematically evaluated potential mechanisms involved in development of the behavioral changes produced by chromic gut ligatures loosely tied around the sciatic nerve. Four ligatures of either silk (4-0), plain gut (4-0), or chromic gut (4-0, 3-0, or 2-0) were placed loosely around the left sciatic nerve of male Sprague-Dawley rats. An additional group of rats had 8 x 0.5 cm sections of 4-0 chromic gut laid adjacent to the left sciatic nerve. The right sciatic nerve was exposed in all rats for sham surgery. The posture and gait of all rats was qualitatively assessed before (day 0) and for 20-30 days after surgery. Rats were tested for evidence of thermal and mechanical hyperalgesia prior to surgery, and on postoperative days 3, 5, 10, 20 and, in some groups, on day 30. Chromic gut, but not plain gut or silk, ligatures placed around or laid next to the sciatic nerve produced an alteration in the posture of rats such that most of the pressure was placed on the heel and medial aspect of the left (ligated) hind paw with the toes held together and plantar-flexed while pressure appeared to be evenly distributed on the right (sham) hind paw. As a result, a pronounced limp was evident, often with the left hind paw held in the air for prolonged periods of time during the first few days after surgery. These postural changes were most pronounced in the 2-0 and 3-0 chromic gut-treated rats. Chromic gut sutures (4-0, 3-0, or 2-0) tied loosely around the left sciatic nerve also produced a 'dose-dependent' decrease in thermal withdrawal latency that was maximal on postoperative day 3 (25%, 39%, and 41%, respectively). The magnitude of the thermal hyperalgesia declined over time such that a return to baseline was observed by postoperative day 20 in 4-0 and 3-0 chromic gut-treated rats.(ABSTRACT TRUNCATED AT 400 WORDS)

Several recent reports document that activation of the NMDA receptor is required for the development and maintenance of thermal hyperalgesia. In contrast, the receptor subtype(s) involved in mechanisms that underlie mechanical hyperalgesia are at present unknown. We report here that acute mechanical hyperalgesia in the rat is not produced by NMDA receptor agonists, but instead requires coactivation of ionotropic AMPA and metabotropic glutamate receptor subtypes. Collectively, the results are consistent with a role for activation of spinal cord neurons using NMDA receptor agonists in mechanisms of thermal hyperalgesia and for coactivation of AMPA and metabotropic glutamate receptors on spinal cord neurons in mechanisms of mechanical hyperalgesia.

Recent observations using acute and persistent pain models have suggested that activation of the N-methyl-D-aspartate (NMDA) receptor is required for mechanisms that underly the development and maintenance of thermal hyperalgesia. The present results document that both NMDA-mediated thermal hyperalgesia produced after acute intrathecal NMDA administration and NMDA-mediated thermal hyperalgesia produced in a model of neuropathic pain are dose-dependently and reversibly attenuated by intrathecal administration of ethanol (0.5-1.0%; total dose, 106-213 nmol, i.t.). This is consistent with recent reports that ethanol may function as a selective NMDA receptor antagonist at low concentrations and further extends the evidence that thermal hyperalgesia is mediated by NMDA receptors.

Loose ligation of the sciatic nerve with 4-0 chromic gut sutures in rats produces behavioral evidence of neuropathic pain. In the present experiments we examined the involvement of capsaicin-sensitive afferents in mediating the thermal hyperalgesia produced by this model. Male Sprague-Dawley rats, treated as neonates (within 48 h of birth) with capsaicin (50 mg/kg, s.c.) or vehicle, were used at 16-18 weeks of age. Chromic gut sutures (4-0) were tied around the left sciatic nerve and withdrawal latencies of both hind paws to radiant heat were determined on postoperative days 3, 5, 10 and 20. Whereas there was a pronounced thermal hyperalgesia which lasted for up to 20 days in vehicle-treated rats, there was no evidence of thermal hyperalgesia in capsaicin-treated rats. There was no difference in baseline (pre-surgery) withdrawal latencies between the two groups. Radioimmunoassay revealed that there was a significant depletion of substance P (43.8%) and calcitonin-gene-related peptide (72.6%) in the lumbar spinal cord of neonatal capsaicin-treated rats compared to vehicle-treated rats. These results demonstrate that the chromic gut-induced thermal hyperalgesia is mediated by capsaicin-sensitive afferents and suggest that central mechanisms which process and control the reflex response to heat are different than mechanisms involved in thermal hyperalgesia.

Bradykinin (BK) is a potent algesic compound. Therefore, we hypothesized that BK, acting as a peripheral noxious stimulus, would attenuate or inhibit responses to another noxious stimulus. When administered intravenously (i.v.) to rats lightly anesthesized with pentobarbital, BK produced a dose-dependent (12-144 micrograms/kg) inhibition of the nociceptive tail-flick (TF) reflex. BK also produced a dose-dependent decrease in mean arterial blood pressure, a subsequent increase in heart rate and an increase in the rate of respiration. The latency to the maximal effect of BK on the TF reflex was 10 s and was occasionally preceded by pseudoaffective responses at doses greater than 48 micrograms/kg BK. Neonatal treatment with capsaicin (50 mg/kg, subcutaneous) significantly attenuated BK-produced inhibition of the TF reflex indicating that BK was acting via peripheral afferents to inhibit the TF reflex. Reversible cold block or complete spinal transection at a low thoracic level (T9-12), but not reversible cold block at a high cervical level (C1-2), significantly attenuated BK-produced inhibition of the TF reflex, suggesting that BK activates afferents which enter the spinal cord between C2 and T9. Pretreatment with intrathecally administered phentolamine (30 micrograms), an alpha-adrenoceptor antagonist, or methysergide (30 micrograms), a non-selective serotonin receptor antagonist, did not alter BK-produced inhibition of the TF reflex, further supporting the absence of activation of descending systems from the brainstem by i.v. BK. While coadministration of PGE2 and BK significantly potentiated BK-produced inhibition of the TF reflex, neither bilateral removal of the stellate ganglion nor bilateral cervical vagotomy significantly affected the inhibitory action of i.v. BK on the TF reflex. These results suggest that i.v. BK inhibits the nociceptive TF reflex by activation of capsaicin-sensitive visceral afferents entering the spinal cord between C2 and T9.

The intrathecal (i.t.) administration of either N-methyl-D-aspartate (NMDA, 10 fmol to 10 pmol) or L-arginine (1 pmol to 10 nmol), but not D-arginine (1 pmol to 10 nmol), produced a rapid, transient, dose-dependent facilitation (maximal response of 30.9 +/- 6.0% and 33.7 +/- 1.5%, respectively) of the nociceptive tail-flick reflex (ED50 = 47.8 +/- 15.4 fmol and 11.4 +/- 2.7 pmol, respectively). Maximal NMDA-produced facilitation of the tail-flick reflex (1 pmol i.t.) was completely abolished by prior treatment (10 min prior) with either N omega-nitro-L-arginine methyl ester (L-NAME, 10 nmol i.t.), methylene blue (10 nmol i.t.) or DL-5-aminophosphonovaleric acid (AP5, 100 pmol i.t.). NMDA-produced facilitation was completely recovered 40 min after L-NAME, 50 min after methylene blue and 30 min after AP5. L-NAME, methylene blue or AP5 did not significantly alter baseline tail-flick latency. These results suggest that NMDA-produced facilitation of a thermal nociceptive reflex is mediated through activation of an NMDA receptor that results in an increase in endogenous nitric oxide and activation of soluble guanylate cyclase in lumbar spinal cord.

Many of the circulating algesic agents released in response to ischemia produce a profound vasodilatation possibly through the release of an endothelium-derived relaxing factor (EDRF) as well as pain. We report here that intravenously administered S-nitrosocysteine, a putative EDRF, and not the nitric oxide liberating compound sodium nitroprusside produces significant alterations in nociceptive behavior that are abolished by bilateral vagotomy. These results are consistent with a role for EDRF in peripheral nociceptive mechanisms.