Significant Antiallodynic Effect Research Articles

The Effect of Pulsed Radiofrequency Current on Mechanical Allodynia Induced with Resiniferatoxin in Rats

Pulsed radiofrequency (PRF) is a popular pain treatment modality. The effect of PRF current on neuropathic pain has not been examined in detail. We investigated the effect of PRF current on mechanical allodynia induced with resiniferatoxin (RTX) in rats, especially regarding the influence of the duration of allodynia before PRF procedures and that of exposure time to PRF. Adult male Sprague-Dawley rats (weighing 250-400 g) received a single intraperitoneal injection of RTX (200 microg/kg) under 2 to 3% sevoflurane anesthesia. Rats in group S(2) (n = 5) were assigned to receive PRF current to the right sciatic nerve for 2 minutes 1 week after RTX treatment; rats in group M(2) (n = 6), PRF current for 2 minutes 3 weeks after RTX treatment; rats in group L(2) (n = 7), PRF current for 2 minutes 5 weeks after RTX treatment; rats in group S(4) (n = 5), PRF current for 4 minutes 1 week after RTX treatment; rats in group S(6) (n = 5), PRF current for 6 minutes 1 week after RTX treatment; and rats in group S(0) (n = 3), no PRF current was delivered. Instead, the needle and electrode were inserted at proper points for 6 minutes 1 week after RTX treatment. All rats were evaluated for sensitivity to mechanical stimulation with von Frey filaments and to thermal stimulation with a thermal testing apparatus and for motor function using placing and grasping reflexes before injection of RTX, every week after injection of RTX, and 1, 2, 3, 4, and 5 weeks after PRF treatment. The paw withdrawal thresholds of both hindpaws 1 week after RTX treatment were significantly lower than the pre-RTX baseline in all groups. In groups S(2), S(4), S(6), and M(2), after PRF procedures, the ipsilateral paw withdrawal thresholds significantly increased. A statistically significant difference was detected between the PRF-treated and PRF-untreated hindpaws. The ipsilateral-contralateral paw withdrawal thresholds after PRF procedures in group S(2) were significantly higher than those in groups M(2) and L(2). Between groups M(2) and L(2), significant differences were found 1, 2, 4, and 5 weeks after PRF procedures. The ipsilateral-contralateral paw withdrawal thresholds in group S(6) were significantly higher than those in groups S(2) and S(4) 5 weeks after PRF procedures. No significant difference was found between groups S(2) and S(4) at any time. After PRF procedures, no difference in the withdrawal latency after heat stimulation and no motor disturbance were observed at any time in all groups. PRF treatment was more effective when applied in the early stages of mechanical allodynia (1 week) in rats. Increased exposure time to PRF current from 2 to 6 minutes showed a significant antiallodynic effect without motor impairment. We propose the application of PRF current for 6 minutes adjacent to the nerve as soon as possible when allodynia appears.

In vivo relationship between thalamic nicotinic acetylcholine receptor occupancy rates and antiallodynic effects in a rat model of neuropathic pain: Persistent agonist binding inhibits the expression of antiallodynic effects

We have recently clarified that nicotinic acetylcholine receptors (nAChRs) expressed in the thalamus play an important role in antiallodynic effects produced by the nAChR agonist, 5-iodo-3-(2(S)-azetidinylmethoxy)pyridine (5IA). This study aimed to reveal the in vivo relationship between thalamic nAChR occupancy rates and antiallodynic effects using 5IA and [¹²⁵I]5IA. We partially ligated the sciatic nerve of a rat to induce neuropathic pain. Antiallodynic effects were evaluated at 15, 30, 60, and 90 min after intracerebroventricular (i.c.v.) administration of multiple doses (1-100 nmol) of 5IA by the von Frey filament test. Receptor occupancy rates were measured by autoradiography at 15 and 90 min after administration. Antiallodynic effects of repetitive treatment of 5IA (5 and 50 nmol) were also examined. A significant and dose-dependent antiallodynic effect was observed 15 min after administration. It showed a good correlation with receptor occupancy rates (r = 0.97), indicating the binding of 5IA to nAChRs expressed in the thalamus involved in the antiallodynic effect. Five, 50, and 100 nmol of 5IA occupied the thalamic nAChRs until 90 min after administration, while the antiallodynic effect diminished. Five nanomoles of 5IA (which occupied 40% of thalamic nAChRs) showed a significant antiallodynic effect (percentage of the maximal possible effect (%MPE): 35 ± 7) after the second administration, while 50 nmol of 5IA (which occupied 80% of thalamic nAChRs) did not (%MPE: 7 ± 1). These findings suggest that not clearance of 5IA but desensitization of nAChRs caused by persistent binding of 5IA is responsible for the disappearance of antiallodynic effects.

Pharmacological Evaluation of Analgesic Effects of the Cholecystokinin2 Receptor Antagonist Z-360 in Mouse Models of Formalin- and Cancer-Induced Pain

Z-360, a novel cholecystokinin(2) (CCK(2)) receptor antagonist, has been developed as a therapeutic drug for pancreatic cancer and showed pain relief action in phase Ib/IIa clinical trial. This study was attempted to elucidate the analgesic efficacy of Z-360 in mice. Oral administration of Z-360 (30-300 mg/kg) showed a dose-dependent inhibitory effect on the late phase of nociceptive responses to formalin. YF476, another CCK(2) receptor antagonist, was without effects at 1 and 10 mg/kg. In contrast, the CCK(1) receptor antagonist devazepide inhibited the nociceptive responses to formalin. In a mouse model of cancer pain, significant anti-allodynic effect of Z-360 was observed after single and repeated oral administration of 100 and 300 mg/kg doses. Anti-allodynic effect was also observed after repeated administration of devazepide. Combined single treatment with morphine and Z-360 caused an increase inhibition of pain-related responses in the pain models produced by formalin and cancer. Although Z-360 has lower affinity for CCK(1) receptor than for CCK(2) receptor, Z-360 exhibited an inhibitory effect on sulfated CCK-8-induced gallbladder emptying, a CCK(1) receptor-mediated effect, at a dose of 100 mg/kg. These results suggest that Z-360 inhibits inflammatory and cancer pain probably through the blockade of CCK(1) receptors. Z-360 is expected to become a useful drug for the pancreatic cancer with analgesic effects as well as the prolongation of survival.

Oral pregabalin reverses cold allodynia in two distinct models of peripheral neuropathic pain

A major symptom of persistent neuropathic pain, which may develop after peripheral nerve injury, is hypersensitivity (allodynia) to normally innocuous cold stimuli. Although the anticonvulsant pregabalin has been demonstrated to relieve neuropathic pain, both in preclinical models and clinically, the analgesic effect of the drug in animals has not been profiled for cold hypersensitivity. Therefore, we examined the effect of pregabalin (single oral dosing: 30, 100, 300 μmol/kg) on cold allodynia in two models of chronic neuropathic pain, the spared nerve injury (SNI) and the spinal nerve ligation (SNL) models. A significant antiallodynic effect was observed with pregabalin at all doses tested with a maximal effect of 71% (SNI) and 60% (SNL), respectively compared to vehicle. For comparison, only the highest dose tested of pregabalin (300 μmol/kg), significantly decreased pain responses in phase 2 of the rat formalin test (∼ 67% pain inhibition). However, pregabalin at this high dose also affected other centrally mediated behavioural functions, such as motor activity and anxiolytic behaviour in naïve animals, which could potentially interfere with the pain readout. The present study demonstrates that oral administration of pregabalin significantly reduces both cold allodynia induced in the SNI and the SNL models of neuropathic pain as well as formalin-induced nociception, albeit with different sensitivity and potency.

The proteinase inhibitor camostat mesilate suppresses pancreatic pain in rodents

Camostat mesilate, an orally available proteinase inhibitor, is clinically used for treatment of pancreatitis. Given recent evidence that pancreatic proteinases including trypsin and/or proteinase-activated receptor-2 (PAR2) might be involved in pancreatic pain, we examined if camostat mesilate could suppress spinal Fos expression, a marker for neuronal activation, following specific application of trypsin to the pancreas, and pancreatitis-related referred allodynia. Trypsin, administered into the pancreatic duct, caused delayed expression of Fos proteins in the superficial layer of the bilateral T8 and T9 spinal dorsal horns in rats. The trypsin-induced spinal Fos expression was completely abolished by oral pre-administration of camostat mesilate at 300 mg/kg. After hourly repeated (6 times in total) administration of caerulein, mice showed typical symptoms of pancreatitis, accompanied by mechanical allodynia in the upper abdomen (i.e., referred hyperalgesia/allodynia), as assessed by use of von Frey filaments. Camostat mesilate at 100–300 mg/kg, given orally twice before the 1st and 4th doses of caerulein, abolished the pancreatitis-related abdominal allodynia, while it partially prevented the inflammatory signs. The same doses of camostat mesilate, when administered once after the final dose of caerulein, also revealed significant anti-allodynic effect. These data suggest that camostat mesilate prevents and/or depresses pancreatitis-induced pain and/or referred hyperalgesia/allodynia, in which proteinases including trypsin would play a critical role.

The function neutralizing anti-TrkA antibody MNAC13 reduces inflammatory and neuropathic pain

Nerve growth factor (NGF) is involved in pain transduction mechanisms and plays a key role in many persistent pain states, notably those associated with inflammation. On this basis, both the NGF ligand and its receptor TrkA (tyrosine kinase A) represent an eligible target for pain therapy. Although the direct involvement of NGF in pain modulation is well established, the effect of a direct functional block of the TrkA receptor is still unknown. In this study, we have demonstrated that MNAC13, the only anti-TrkA monoclonal antibody for which function neutralizing properties have been clearly shown both in vitro and in vivo, induces analgesia in both inflammatory and neuropathic pain models, with a surprisingly long-lasting effect in the latter. The formalin-evoked pain licking responses are significantly reduced by the MNAC13 antibody in CD1 mice. Remarkably, treatment with the anti-TrkA antibody also produces a significant antiallodynic effect on neuropathic pain: repeated i.p. injections of MNAC13 induce significant functional recovery in mice subjected to sciatic nerve ligation, with effects persisting after administration. Furthermore, a clear synergistic effect is observed when MNAC13 is administered in combination with opioids, at doses that are not efficacious per se. This study represents a direct demonstration that neutralizing antibodies directed against the TrkA receptor may display potent analgesic effects in inflammatory and chronic pain.

Novel therapeutic agents: Gene transfer of interleukin-4 (IL-4) produces persistent antinociception and suppresses the induction of spinal PGE2 in neuropathic pain

Inflammatory cytokines (e.g. TNF alpha, IL-1 beta and IL-6) and prostaglandin E2 in spinal cord appear to play a role in the neuropathic pain. Interleukin-4 (IL-4) is an anti-inflammatory cytokine that inhibits production of TNF alpha, IL-1 and IL-6, among other actions. In the present study, we examined the effect of herpes simplex virus (HSV)-based vector-mediated transfer of the gene coding for IL-4 (vector S4IL4) to lumbar DRG in rats with neuropathic pain. Primary DRG neurons in culture transduced with S4IL4 released IL-4 into the medium measured by ELISA. Subcutaneous inoculation of S4IL4 into the paw resulted in expression of IL-4 in L4-6 DRG and sciatic nerve in vivo detected by ELISA. Mechanical threshold was determined by stimulation of the plantar surface of the hindpaw with graded von Frey monofilaments; the threshold was established using the up-down method (Dixon). Thermal latency was assessed by thermal evoked paw withdrawal. In normal rats, neither vector expressing IL-4 nor control vector changed mechanical threshold or thermal latency. Selective L5 spinal nerve ligation (SNL) resulted in neuropathic pain characterized by mechanical allodynia and thermal hyperalgesia. Subcutaneous inoculation of vector S4IL4 produced a significant antiallodynic effect and reversed thermal hyperalgesia. Inoculation with a control HSV vector carrying the lacZ reporter transgene in the tk locus (vector SHZ) did not alter either mechanical threshold or thermal latency. Inoculation of S4IL4 one week prior to SNL delayed development of tactile allodynia and thermal hyperalgesia. Inoculation of S4IL4 suppressed gentle touch-induced expression of c-fos immunoreactivity in spinal cord. Inoculation of S4IL4 suppressed upregulation of spinal IL-1 beta and prostaglandin E2 in rats with neuropathic pain. The results demonstrate that recombinant herpes virus expressing IL-4 may be antinociceptive in the neuropathic pain.

A single intravenous injection of KRN5500 (antibiotic spicamycin) produces long-term decreases in multiple sensory hypersensitivities in neuropathic pain.

Neuropathic pain is a significant clinical problem. Currently, there are no drugs that produce complete amelioration of this type of pain. We have previously shown that KRN5500, a derivative of the antibiotic spicamycin, produces a prolonged (7-day), and significant reduction in neuropathic pain, but not nociceptive pain. Herein, we provide further evidence for the efficacy of this drug in inhibiting pain after IV injection in a spared nerve injury model of neuropathic pain. A single IV dose of the drug produces an increase in pain thresholds to punctuate mechanical stimuli and to cold stimuli over a period of 7 days, whereas IV injection of the vehicle is without any effect. No change in pain threshold was observed in the contralateral foot. In addition, a significant antiallodynic effect to mechanical stimuli was observed at 1, 2, 4, and 6 wk. The drug may be a potential candidate for cancer-related neuropathic pain as well as a marker for discovery of effective analgesics for neuropathic pain. We examined the effect of a novel drug (KRN5500) on nerve damage pain. After the successful effects of this drug in a single human, we have shown that the drug infused as a single application at different doses in a rat model of nerve damage pain produces pain relief in this model for many weeks.

Analgesic effects of intrathecal administration of P2Y nucleotide receptor agonists UTP and UDP in normal and neuropathic pain model rats.

Recent electrophysiological, behavioral, and biochemical studies revealed that ATP plays a role in facilitating spinal pain transmission via ionotropic P2X nucleotide receptors, although the involvement of metabotropic P2Y nucleotide receptors remains unclear. In the present study, we examined the effects of i.t. administration of P2Y receptor agonists UTP, UDP, and related compounds on nociception in normal rats and tactile allodynia in a neuropathic pain model. In the paw pressure test using normal rats, i.t. administration of UTP (30 and 100 nmol/rat) and UDP (30 and 100 nmol/rat), but not UMP (100 nmol/rat) or uridine (100 nmol/rat), significantly elevated the mechanical nociceptive thresholds, whereas ATP (30 and 100 nmol/rat) and alpha,beta-methylene-ATP (10 and 30 nmol/rat) lowered them. Similarly, in the tail-flick test, UTP (10, 30, and 100 nmol/rat) and UDP (100 nmol/rat) significantly prolonged the thermal nociceptive latency. In the von Frey filament test on normal rats, UTP (100 nmol/rat) and UDP (100 nmol/rat) produced no allodynia to the tactile stimulus, whereas ATP (100 nmol/rat) induced a significant and long-lasting tactile allodynia. In the neuropathic pain model, in which the sciatic nerves of rats were partially ligated, UTP (30 and 100 nmol/rat) and UDP (30 and 100 nmol/rat) produced significant antiallodynic effects. Furthermore, UTP (100 nmol/rat) and UDP (100 nmol/rat) caused no motor deficit in the inclined plane test. Taken together, these results suggest that the activation of UTP-sensitive P2Y(2) and/or P2Y(4) receptors and the UDP-sensitive P2Y(6) receptor, in contrast to P2X receptors, produces inhibitory effects on spinal pain transmission.

Combined systemic administration of morphine and magnesium sulfate attenuates pain-related behavior in mononeuropathic rats

The response to opioids is reduced in neuropathic pain states. We examined the effect of the combination of morphine (0.1 mg/kg) and magnesium sulfate (125 mg/kg) on behavioral signs of neuropathic pain in spinal nerve ligated rats. Administered alone, neither drug produced any effect, but the combination exerted a significant anti-allodynic effect, which was partially reversed by naloxone. These results suggest that combining low doses of magnesium sulfate with opiates might be an alternative in treating neuropathic pain, with reduced risk of side effects.

Basic Science (27)

Effects of radolmidine, a novel α2‐adrenergicagonist compared with dexmedetomidine in different pain models in the rat. (University of Helsinki, Helsinki, Finland) Anesthesiology 2000;93:473–481.This study determined the antinociceptive and sedative effects of radolmidine in different models of acute and chronic pain. Dexmedetomidine and saline served as controls. Male Sprague‐Dawley rats were studied in acute pain (tail flick), carrageenan inflammation, and the spinal nerve ligation model of neuropathic pain. Mechanical allodynia was assessed with von Frey filaments, cold allodynia with the acetone test, and thermal hyperalgesia with the paw flick test. Locomotor activity‐vigilance was assessed in a dark field. Dexmedetomidine and radolmidine were administered intrathecally in doses of 0.25 μg, 2.5 μg, and 10 μg. In the tail flick test, radolmidine showed a dose‐dependent antinociceptive effect, being equipotent compared with dexmedetomidine. In carrageenan inflammation, intrathecal doses of 2.5 μg or 5 μg of dexmedetomidine/radolmidine produced significant antinociception compared with saline (P < 0.01). The two drugs were equianalgesic. In the neuropathic pain model, an intrathecal dose of 5 μg dexmedetomidine‐radolmidine had a significant antiallodynic effect compared with saline (P < 0.01). The 2 drugs were equipotent. Intrathecal administration of both dexmedetomidine and radolmidine dose dependently decreased spontaneous locomotor activity‐vigilance, but this effect was significantly smaller after intrathecal administration of radolmidine than after intrathecal dexmedetomidine. Conclude radolmidine and dexmedetomidine had equipotent antinociceptive effects in all tests studied. However, radolmidine caused significantly less sedation than dexmedetomidine, probably because of a different pharmacokinetic profile.

Synergistic antiallodynic effects of spinal morphine with ketorolac and selective COX 1- and COX 2-inhibitors in nerve-injured rats

The possible role of spinal prostanoids in the tactile allodynia and thermal hyperalgesia associated with an experimental model of neuropathic pain was investigated. Neuropathic pain was induced by tight ligation of the L5 and L6 spinal nerves. Tactile allodynia was assessed 7 days after the surgery by measuring hindpaw withdrawal threshold to probing with von Frey filaments. Thermal hyperalgesia and nociception were determined by the 52°C warm-water tail-flick test and by applying radiant heat to the plantar aspect of the hindpaw ipsilateral to the ligation. Minimal antiallodynic effect was produced by intrathecal (i.th.) administration of ketorolac or morphine up to the highest testable dose (100 μg) or by the ( R)- or ( S)-enantiomers of ketorolac (up to 6 μg) when administered alone. However, i.th. administration of a fixed ratio (1:1) of morphine plus racemic ketorolac or of morphine plus the ( S)-enantiomer of ketorolac ( S-ketorolac) produced a dose- and time-related antiallodynic effect: ED 50 114±35.9 μg (total dose) for morphine plus ketorolac and 70.5±21.0 μg (total dose) for morphine plus S-ketorolac. The combination of i.th. morphine plus the ( R)-enantiomer of ketorolac ( R-ketorolac) (up to 200 μg total dose) was without effect. Similar antiallodynic activity was obtained for the co-administration of i.th. morphine and intravenous (i.v.) racemic ketorolac. In order to investigate the role of cyclooxygenase (COX) isozymes, relatively selective COX 1 (piroxicam) and COX 2 N-[2-cyclohexyloxy-4-nitrophenyl] metanesulfonamide (NS-398) inhibitors were administered i.th. (60 μg) alone or together with i.th. morphine. Piroxicam, NS-398, morphine and vehicle (90% DMSO) were without significant antiallodynic effect when administered alone, but moderate antiallodynic effects were produced by i.th. administration of fixed ratio (1:1) combinations of morphine with 60 μg each (highest soluble dose) of piroxicam (%MPE=40.8±10.2) or NS-398 (%MPE=32.4±9.5). Further, the combined i.th. administration of morphine, piroxicam and NS-398 in fixed 1:1:1 ratio (60 μg each) resulted in a supraadditive antiallodynic effect (%MPE=70.4±10.8). Finally, morphine, but not ketorolac, given i.th. produced dose-dependent anti nociception in either the tail-flick or the paw-flick tests. However, there was no synergy between morphine and ketorolac against thermal nociception in either of the tests. These findings suggest that spinal prostanoids produced via both COX 1 and COX 2 pathways may play a role in neuropathic pain states and suggest the clinical utility of opioid plus COX-inhibitor combination therapy.

Anti-allodynic actions of intravenous opioids in the nerve injured rat: potential utility of heroin and dihydroetorphine against neuropathic pain

Neuropathic pain has been suggested to be resistant to treatment with opiates. Such perceived lack of opioid responsiveness may be due to the dose-range over which specific opioid compounds have been studied as well as the efficacy of these compounds. Dihydroetorphine is a novel opiate that demonstrates significantly greater analgesic potency compared to morphine, and which also demonstrates diminished capacity for producing physical dependence in laboratory animals. The present study compared the intravenous (i.v.) efficacy, potency and duration of action of dihydroetorphine, fentanyl, heroin and morphine in producing anti-allodynic actions in a rat model of neuropathic pain (ligation of the L5/L6 nerve roots). All compounds produced significant anti-allodynic activity with dihydroetorphine being the most potent ( A 50 of 0.2 μg kg −1, i.v.). Morphine was approximately 7440 times less potent than dihydroetorphine while heroin and fentanyl were approximately 163.5 and 6.9 times less potent in producing anti-allodynic actions. Dihydroetorphine also showed a maximal effect at 0.6 μg kg −1 in all animals tested, while 100 μg kg −1 was required for heroin to produce a maximal effect. Fentanyl and morphine did not elicit a maximum anti-allodynic response (74 and 76%maximum possible effect (%MPE), respectively). As expected, fentanyl showed a relatively brief duration of action (approximately 20 min at the highest tested dose), while dihydroetorphine and morphine demonstrated anti-allodynic actions for up to 45 min. Heroin had the longest duration of action, producing significant anti-allodynic effects for up to 90 min. These data show that dihydroetorphine and heroin produce potent and long-lasting anti-allodynic actions in this model. Additionally, in contrast to morphine and fentanyl, both dihydroetorphine and heroin were able to achieve a maximal response. The remarkable potency, maximal efficacy and duration of action of these compounds, particularly dihydroetorphine, suggests that these compounds may warrant further examination as potential therapeutic treatments for neuropathic pain states.

ABT-594, a novel cholinergic channel modulator, is efficacious in nerve ligation and diabetic neuropathy models of neuropathic pain

A novel cholinergic channel modulator, ABT-594, was tested in two established and distinct models of neuropathic pain; the Chung model (i.e., tight ligation of L5 and L6 spinal nerves) and a diabetic neuropathy model (i.e., streptozotocin-induced diabetes). Tactile allodynia and mechanical hyperalgesia were assessed in the Chung and diabetic neuropathy models, respectively. ABT-594 produced a significant antiallodynic effect following both oral (0.1–1 μmol/kg) and intraperitoneal (i.p.) (0.3 μmol/kg) administration. Equal efficacy was observed following both routes of administration. ABT-594 (0.3 μmol/kg, i.p.) maintained efficacy following repeated dosing (5 days; twice daily) in the Chung model, but the effect of morphine (21 μmol/kg, i.p.) was significantly reduced after repeated dosing. In the diabetic neuropathy model, ABT-594 (0.3 μmol/kg, i.p.) effectively reduced mechanical hyperalgesia. Morphine (21 μmol/kg, i.p.) was not effective in this model. Overall, these results suggest development of ABT-594 may provide a novel pharmacotherapy for the chronic treatment of neuropathic pain.

A differential modulation of allodynia, hyperalgesia and nociception by neuropeptide FF in the periaqueductal gray of neuropathic rats: interactions with morphine and naloxone

The effect of neuropeptide FF in the periaqueductal gray on pain behaviour was studied in rats with a chronic neuropathy induced by unilateral ligation of two spinal nerves. Neuropeptide FF produced in a non-monotonic fashion a significant attenuation of tactile allodynia. The antiallodynic effect was not significantly modulated by naloxone administered systemically or intracerebrally. The dose of neuropeptide FF producing a significant antiallodynic effect was not antinociceptive in a test of mechanical or thermal nociception. The thermal antinociceptive effect induced by morphine administered in the periaqueductal gray was significantly attenuated by neuropeptide FF, whereas that induced by systemically administered morphine was not. The interaction of neuropeptide FF with intracerebrally or systemically administered morphine in a test of tactile allodynia was not significant. The results indicate that neuropeptide FF in the periaqueductal gray may produce a selective attenuation of tactile allodynia in neuropathic rats. This antiallodynic effect is at least partly independent of naloxone-sensitive opioid receptors. Furthermore, neuropeptide FF in the periaqueductal gray attenuates antinociception induced by intracerebrally but not systemically administered morphine.

Lidocaine in the rostroventromedial medulla and the periaqueductal gray attenuates allodynia in neuropathic rats

In the present study we attempted to find out if the rostroventromedial medulla (RVM) or the periaqueductal gray (PAG) might contribute to chronic allodynia induced by unilateral ligation of two spinal nerves in the rat. Lidocaine was microinjected in the RVM or PAG and allodynia was quantitatively determined by measuring the hindlimb withdrawal thresholds to mechanical stimulation of the paw. For comparison, lidocaine was also injected systematically (s.c.). Lidocaine in the RVM produced a dose-related (20 and 40 μg) antiallodynic effect. Lidocaine (20 μg) in the PAG produced identical antiallodynic effect as in the RVM. With systemic administrations of lidocaine, a considerably higher dose (> 40 μg) was needed to produce a significant antiallodynic effect. Naloxone, an opioid-antagonist (1 mg/kg s.c.), did not attenuate the antiallodynic effect of lidocaine in the RVM. An antiallodynic dose of lidocaine (20 μg) in the RVM or the PAG did not influence the withdrawal response in the unoperated hindlimb nor the heat-induced tail-flick reflex. The results indicate that the RVM and the PAG have a facilitatory influence on the spinal segmental mechanisms underlying chronic allodynia. The selective attenuation of allodynia induced by lidocaine in the RVM and the PAG is independent of opiate receptors, and it can not be explained by a systemic spread of the drug.

The loss of antinociceptive efficacy of spinal morphine in rats with nerve ligation injury is prevented by reducing spinal afferent drive

Nerve ligation injury in rats may represent a useful model of some clinical neuropathic pains. Activation of N-methyl- d-aspartate (NMDA) receptors may maintain central sensitivity and contribute to neuropathic pain. Here, nerve injury was produced by unilateral ligation of the L5 and L6 spinal roots of the sciatic nerve of rats. Catheters were inserted for intrathecal (i.th.) or local delivery of drugs at the site of nerve ligation. Acute nociception was measured by the 55°C water tail flick test in sham-operated and nerve-injured rats, and allodynia was determined by measuring response to von Frey filaments. In sham-operated rats, morphine (30 μg, i.th.) produced a 60±14.4% MPE (maximal possible effect). MK-801 pretreatment did not alter tail-flick latency or morphine antinociception in sham-operated rats. In nerve-injured rats, morphine (30 μg, i.th.) produced a significantly lower antinociceptive effect than in controls (34±6.3% MPE). While MK-801 alone did not alter tail-flick latency in nerve-injured rats, it significantly enhanced the antinociceptive effect of morphine to 84±16.0% MPE. Bupivacaine (0.2 ml, 0.75% w/v) at the site of injury also significantly increased the efficacy of morphine (100±0% MPE) without affecting tail flick latency alone. Bupivacaine administered at the site of injury also produced a significant antiallodynic effect of 94±7.4% MPE. The reduction in antinociceptive efficacy of i.th. morphine in nerve injured rats may due, in part, to an ongoing spontaneous activity initiated by ectopic foci at the site of injury, and possible NMDA receptor-mediated activation of spinal neurons.