Glutamate receptor ligands attenuate allodynia and hyperalgesia and potentiate morphine effects in a mouse model of neuropathic pain

Recent studies have indicated that metabotropic glutamate receptors mGluR5, mGluR2/3 and mGluR7 are present in the regions of central nervous system important for nociceptive transmission, but their involvement in neuropathic pain has not been well established. We demonstrated that acute and chronic administration of MPEP (mGluR5 antagonist), LY379268 (mGluR2/3 agonist), and AMN082 (mGluR7 agonist) attenuated allodynia (von Frey test) and hyperalgesia (cold plate test) as measured in Swiss albino mice on day seven after chronic constriction injury (CCI) to the sciatic nerve. Moreover, single administration of MPEP (30 mg/kg; i.p.) or LY379268 (10mg/kg; i.p.) injected 30 min before morphine potentiated morphine's effects (20mg/kg; i.p.) in the mouse CCI model, as measured by both the tests mentioned above. However, a single administration of AMN082 (3mg/kg; i.p.) potentiated the effects of a single morphine injection (20mg/kg; i.p.) in the von Frey test only. Chronic administration (7 days) of low doses of MPEP, LY379268 or AMN082 (all drugs at 3mg/kg; i.p.) potentiated the effects of single doses of morphine (3, 10, and 20mg/kg; i.p.) administered on day seven; however, AMN082 only potentiated the effect in the cold plate test. Additionally, the same doses of MPEP and LY379268 (but not AMN082) chronically co-administered with morphine (40 mg/kg; i.p.) attenuated the development of morphine tolerance in CCI-exposed mice. Our data suggest that mGluR5, mGluR2/3, and mGluR7 are involved in injury-induced plastic changes in nociceptive pathways and that the mGluR5 and mGluR2/3 ligands enhanced morphine's effectiveness in neuropathy, which could have therapeutic implications.     

Anti-allodynic effect of NW-1029, a novel Na(+) channel blocker,in experimental animal models of inflammatory and neuropathic pain

NW-1029, a benzylamino propanamide derivative, was selected among several molecules of this chemical class on the basis of its affinity for the [(3)H]batracotoxin ligand displacement of the Na(+) channel complex and also on the basis of its voltage and use-dependent inhibitory action on the Na(+) currents of the rat DRG (dorsal root ganglia) sensory neuron. This study evaluated the analgesic activity of NW-1029 in animal models of inflammatory and neuropathic pain (formalin test in mice, complete Freund's adjuvant and chronic constriction injury in rats) as well as in acute pain test (hot-plate and tail-flick in rats). Orally administered NW-1029 dose-dependently reduced cumulative licking time in the early and late phase of the formalin test (ED(50)=10.1 mg/kg in the late phase). In the CFA model, NW-1029 reversed mechanical allodynia (von Frey test) after both i.p. and p.o. administration (ED(50)=0.57 and 0.53 mg/kg), respectively. Similarly, NW-1029 reversed mechanical allodynia in the CCI model after both i.p. and p.o. administration yielding an ED(50) of 0.89 and 0.67 mg/kg, respectively. No effects were observed in the hot-plate and tail-flick tests up to 30 mg/kg p.o. The compound orally administered (0.1-10 mg/kg) was well tolerated, without signs of neurological impairment up to high doses (ED(50)=470 and 245 mg/kg in rat and mice Rotarod test, respectively). These results indicate that NW-1029 has anti-nociceptive properties in models of inflammatory and neuropathic pain.     

Gabapentin and pregabalin, but not morphine and amitriptyline, block both static and dynamic components of mechanical allodynia induced by streptozocin in the rat

A single injection of streptozocin (50 mg/kg, i.p.) led to the development of static and dynamic allodynia in the rat. The two responses were detected, respectively, by application of pressure using von Frey hairs or lightly stroking the hind paw with a cotton bud. Static allodynia was present in the majority of the animals within 10 days following streptozocin. In contrast, dynamic allodynia took almost twice as long to develop and was only present in approximately 60% of rats. Morphine (1-3 mg/kg, s.c.) and amitriptyline (0.25-2.0 mg/kg, p.o.) dose-dependently blocked static allodynia. However, neither of the compounds was effective against dynamic allodynia. In contrast, gabapentin (10-100 mg/kg, p.o.) and the related compound pregabalin (3-30 mg/kg, p.o.) dose-dependently blocked both types of allodynia. However, the corresponding R-enantiomer (10-100 mg/kg, p.o.) of pregabalin, was found to be inactive. The intrathecal administration of gabapentin dose-dependently (1-100 microg/animal) blocked both static and dynamic allodynia. In contrast, administration of similar doses of gabapentin into the hind paw failed to block these responses. It is suggested that in this model of neuropathic pain dynamic allodynia is mediated by A beta-fibres and the static type involves small diameter nociceptive fibres. These data suggest that gabapentin and pregabalin possess a superior antiallodynic profile than morphine and amitriptyline, and may represent a novel class of therapeutic agents for the treatment of neuropathic pain.     

N-(4-Tertiarybutylphenyl)-4-(3-cholorphyridin-2-yl)tetrahydropyrazine -1(2H)-carbox-amide (BCTC), a novel,orally effective vanilloid receptor 1 antagonist with analgesic properties: II. in vivo characterization in rat models of inflammatory and neuropathic pain

The vanilloid receptor 1 (VR1) is a cation channel expressed predominantly by nociceptive sensory neurons and is activated by a wide array of pain-producing stimuli, including capsaicin, noxious heat, and low pH. Although the behavioral effects of injected capsaicin and the VR1 antagonist capsazepine have indicated a potential role for VR1 in the generation and maintenance of persistent pain states, species differences in the molecular pharmacology of VR1 and a limited number of selective ligands have made VR1 difficult to study in vivo. N-(4-Tertiarybutylphenyl)-4-(3-cholorphyridin-2-yl)tetrahydropryazine-1(2H)-carbox-amide (BCTC) is a recently described inhibitor of capsaicin- and acid-mediated currents at rat VR1. Here, we report the effects of BCTC on acute, inflammatory, and neuropathic pain in rats. Administration of BCTC (30 mg/kg p.o.) significantly reduced both mechanical and thermal hyperalgesia induced by intraplantar injection of 30 micro g of capsaicin. In rats with Freund's complete adjuvantinduced inflammation, BCTC significantly reduced the accompanying thermal and mechanical hyperalgesia (3 mg/kg and 10 mg/kg p.o., respectively). BCTC also reduced mechanical hyperalgesia and tactile allodynia 2 weeks after partial sciatic nerve injury (10 and 30 mg/kg p.o.). BCTC did not affect motor performance on the rotarod after administration of doses up to 50 mg/kg p.o. These data suggest a role for VR1 in persistent and chronic pain arising from inflammation or nerve injury.     

Intrathecal administration of NTS1 agonists reverses nociceptive behaviors in a rat model of neuropathic pain

Chronic neuropathic pain arising from peripheral nerve damage is a severe clinical issue where there is a major unmet medical need. We previously demonstrated that both neurotensin (NT) receptor subtypes 1 (NTS1) and 2 (NTS2) are involved in mediating the naloxone‐insensitive antinociceptive effects of neurotensin in different analgesic tests including hotplate, tail‐flick, and tonic pain. However, the role of these receptors in neuropathic pain management has been poorly investigated. In the present study, we therefore examined whether intrathecal delivery of NTS1 agonists was effective in reducing neuropathic pain symptoms in rats. Neuropathy was induced by sciatic nerve constriction (CCI model), and the development of mechanical allodynia and thermal hyperalgesia on the ipsi‐ and contralateral hind paws was examined 3, 7, 14, 21, and 28 days post‐surgery. CCI‐operated rats exhibited significant increases in thermal and mechanical hypersensitivities over a 28‐day testing period. Spinal injection of NT to CCI rats alleviated the behavioral responses to radiant heat and mechanical stimuli, with a maximal reversal of 91% of allodynia at 6 μg/kg. Intrathecal administration of the NTS1‐selective agonist, PD149163 (30–90 μg/kg) also produced potent anti‐allodynic and anti‐hyperalgesic effects in nerve‐injured rats. Likewise, heat hyperalgesia and tactile allodynia produced by CCI of the sciatic nerve were fully reversed by the NTS1 agonist, NT69L (5–25 μg/kg). Altogether, these results support the idea that the NTS1 receptor subtype is involved in pain modulation, and the potential use of NTS1 agonists for the treatment of painful neuropathies.     

Evaluation of selective NK(1) receptor antagonist CI-1021 in animal models of inflammatory and neuropathic pain

CI-1021 ([(2-benzofuran)-CH(2)OCO]-(R)-alpha-MeTrp-(S)-NHCH(CH (3))Ph) is a selective and competitive neurokinin-1 (NK(1)) receptor antagonist. This study examines its activity in animal models of inflammatory and neuropathic pain. In mice, CI-1021 (1-30 mg/kg, s.c.) dose dependently blocked the development of the late phase of the formalin response with a minimum effective dose (MED) of 3 mg/kg. Two chemically unrelated NK(1) receptor antagonists, CP-99,994 (3-30 mg/kg) and SR 140333 (1-100 mg/kg), also dose dependently blocked the late phase, with respective MEDs of 3 and 10 mg/kg. PD 156982, a NK(1) receptor antagonist with poor central nervous system penetration, failed to have any effect. However, when administered i. c.v., it selectively blocked the late phase of the formalin response. Chronic constrictive injury (CCI) to a sciatic nerve in the rat induced spontaneous pain, thermal and mechanical hyperalgesia, and cold, dynamic, and static allodynia. CI-1021 (10-100 mg/kg) and morphine (3 mg/kg) blocked all the responses except dynamic allodynia. Carbamazepine (100 mg/kg) was weakly effective against all the responses. Once daily administration of morphine (3 mg/kg, s. c.) in CCI rats led to the development of tolerance within 6 days. Similar administration of CI-1021 (100 mg/kg, s.c.) for up to 10 days did not induce tolerance. Moreover, the morphine tolerance failed to cross-generalize to CI-1021. CI-1021 blocked the CCI-induced hypersensitivity in the guinea pig, with a MED of 0.1 mg/kg, p.o. CI-1021 (10-100 mg/kg, s.c.) did not show sedative/ataxic action in the rat rota-rod test. It is suggested that NK(1) receptor antagonists possess a superior side effect profile to carbamazepine and morphine and may have a therapeutic use for the treatment of inflammatory and neuropathic pain.     

The effects of mexiletine,desipramine and fluoxetine in rat models involving central sensitization

Drugs that are clinically effective (mexiletine and desipramine) or ineffective (fluoxetine) in the treatment of human neuropathic pain were evaluated for efficacy in rat models involving central sensitization (i.e., formalin model and the L5/L6 spinal nerve ligation model of neuropathic pain) using tests that differ in stimulus modality: noxious chemical stimulus (formalin model) as well as noxious (pin prick) and innocuous mechanical stimuli (application of von Frey filaments). Mexiletine (10–100 mg/kg, s.c.) significantly (P<0.05) attenuated hyperalgesia in formalin-treated (60 mg/kg and 100 mg/kg) and neuropathic rats (100 mg/kg) as well as tactile allodynia in neuropathic rats (100 mg/kg). Desipramine (1–100 mg/kg, s.c.), on the other hand, reduced hyperalgesia significantly (P<0.05) in formalin-treated (3, 10, 30 and 100 mg/kg) and neuropathic rats (10 mg/kg and 100 mg/kg), but did not reduce tactile allodynia in the neuropathic rats. Fluoxetine (3–30 mg/kg, s.c.) did not inhibit either hyperalgesia or allodynia in any of the tests employed. Fluoxetine, which is relatively ineffective in reducing neuropathic pain in humans, was also ineffective in reducing hyperalgesia and allodynia associated with central sensitization in rats. Thus, drugs which are effective in reducing human neuropathic pain consistently attenuated hyperalgesia in formalin-treated or neuropathic rats. Desipramine also distinguished mechanical hyperalgesia from tactile allodynia in rats rendered neuropathic by spinal nerve ligation. These data are consistent with the hypothesis that the neuronal mechanisms underlying these two manifestations of neuropathic pain are different     

Evidence that CB-1 and CB-2 cannabinoid receptors mediate antinociception in neuropathic pain in the rat

The roles of the two cannabinoid receptor subtypes, CB-1 and CB-2, have not been clarified in cannabinoid-mediated analgesia. We investigated the efficacy of the non-selective cannabinoid receptor agonist CP55,940 in the modulation of responses in the rat to both acute pain (tail flick) and neuropathic pain (tactile allodynia following chronic L5/6 spinal nerve ligation). Responses were also assessed in the presence of the CB-1 antagonist SR141716A (SR1) and the CB-2 antagonist SR144528 (SR2). CP55,940 attenuated tactile allodynia (ED(50) 0.04 mg/kg i.t. (95% CI 0.032-0.044 mg/kg), 0.12 mg/kg i.p. (95% CI 0.10-0.15 mg/kg)) and induced thermal antinociception (ED(50) tail flick 0.07 mg/kg i.t. (95% CI 0.05-0.10 mg/kg), 0.17 mg/kg i.p. (95% CI 0.11-0.26 mg/kg)). SR1 0.5 mg/kg i.t. attenuated the antinociceptive effect of CP55,940 in both modalities. However, SR1 1.0 mg/kg i.p. decreased tail flick latency but had no effect on tactile allodynia antinociception. In contrast, SR2 1.0 mg/kg i.p. significantly decreased the effect of i.p. CP55,940 on both tail flick antinociception and tactile allodynia (P<0.005). The combination of SR1 and SR2 (i.p.) had an additive effect in decreasing the antinociception induced by CP55,940 on tail flick responses (P<0.005). These results suggest a role for CB-2 receptor-mediated antinociception in both acute and neuropathic pain in addition to centrally located CB-1 mechanisms.     

Nitecapone reduces development and symptoms of neuropathic pain after spinal nerve ligation in rats1

Neuropathic pain is caused by damage or malfunctioning of the nervous system. It is fairly common and more resistant to treatment than other types of pain. Since nitecapone, an inhibitor of catechol‐O‐methyl‐transferase (COMT), has decreased neuropathic symptoms in diabetic rats, we studied its effects in another model of neuropathic pain, the spinal nerve ligation (SNL) model. Spinal nerves L5–6 were ligated in male Wistar rats under anaesthesia to produce the SNL model of neuropathic pain. Nitecapone (30 mg/kg, i.p.) or vehicle was administered once daily starting either 1 h before or 2 days after surgery and continued for 14–19 days. Threshold for mechanical allodynia was measured with the digital von Frey test and responses to cold stimuli with the acetone test, before surgery and every other day after it 1 h before drug administration. Mechanical and cold allodynia developed in all study groups. Both nitecapone treatments significantly reduced mechanical allodynia and withdrawal thresholds were 80–95% higher compared with the control group. In the acetone test, both nitecapone groups also showed less signs of cold allodynia than the control groups. In nitecapone‐naïve animals a single dose of nitecapone also reduced mechanical allodynia on the 14th day after the surgery. Nitecapone reduced the symptoms of neuropathic pain after the SNL, which is in line with the earlier study. Our results suggest that nitecapone and other COMT inhibitors should be studied further in the treatment of neuropathic pain.     

Tetrodotoxin inhibits the development and expression of neuropathic pain induced by paclitaxel in mice

We evaluated the effect of low doses of systemically administered tetrodotoxin (TTX) on the development and expression of neuropathic pain induced by paclitaxel in mice. Treatment with paclitaxel (2 mg/kg, i.p., once daily during 5 days) produced long-lasting (2–4 weeks) heat hyperalgesia (plantar test), mechanical allodynia (electronic Von Frey test) and cold allodynia (acetone drop method), with maximum effects observed on days 7, 10 and 10–14, respectively. Acute subcutaneous treatment with 1 or 3 μg/kg of TTX reduced the expression of mechanical allodynia, whereas higher doses (3 or 6 μg/kg) were required to reduce the expression of cold allodynia and heat hyperalgesia. In contrast, TTX (3 or 6 μg/kg, s.c.) did not affect the response to the same thermal and mechanical stimuli in control animals, which indicates that the antihyperalgesic and antiallodynic effects of TTX were not due to unspecific inhibition of the perception of these stimuli. Administration of TTX (6 μg/kg, s.c.) 30 min before each of the 5 doses of paclitaxel did not modify the development of heat hyperalgesia produced by the antineoplastic, but abolished the development of mechanical and cold allodynia. Coadministration of a lower dose of TTX (3 μg/kg) also prevented the development of mechanical allodynia. No signs of TTX-induced toxicity or motor incoordination were observed. These data suggest that low doses of TTX can be useful to prevent and treat paclitaxel-induced neuropathic pain, and that TTX-sensitive subtypes of sodium channels play a role in the pathogenesis of chemotherapy-induced neuropathic pain.     

Injury discharges regulate calcium channel alpha-2-delta-1 subunit upregulation in the dorsal horn that contributes to initiation of neuropathic pain

Previous studies have shown that peripheral nerve injury in rats induces increased expression of the voltage gated calcium channel (VGCC) alpha-2-delta-1 subunit (Ca v alpha2 delta1) in spinal dorsal horn and sensory neurons in dorsal root ganglia (DRG) that correlates to established neuropathic pain states. To determine if injury discharges trigger Ca v alpha2 delta1 induction that contributes to neuropathic pain initiation, we examined allodynia onset and Ca v alpha2 delta1 levels in DRG and spinal dorsal horn of spinal nerve ligated rats after blocking injury induced neural activity with a local brief application of lidocaine on spinal nerves before the ligation. The lidocaine pretreatment blocked ligation-induced discharges in a dose-dependent manner. Similar pretreatment with the effective concentration of lidocaine diminished injury-induced increases of the Ca v alpha2 delta1 in DRG and abolished that in spinal dorsal horn specifically, and resulted in a delayed onset of tactile allodynia post-injury. Both dorsal horn Ca v alpha2 delta1 upregulation and tactile allodynia in the lidocaine pretreated rats returned to levels similar to that in saline pretreated controls 2 weeks post the ligation injury. In addition, preemptive intrathecal Ca v alpha2 delta1 antisense treatments blocked concurrently injury-induced allodynia onset and Ca v alpha2 delta1 upregulation in dorsal spinal cord. These findings indicate that injury induced discharges regulate Ca v alpha2 delta1 expression in the spinal dorsal horn that is critical for neuropathic allodynia initiation. Thus, preemptive blockade of injury-induced neural activity or Ca v alpha2 delta1 upregulation may be a beneficial option in neuropathic pain management.     

背根神经节血红素加氧酶1过表达缓解小鼠神经病理性疼痛

目的:探讨背根神经节(dorsal root ganglion,DRG)中血红素加氧酶1(heme oxygenase 1,HO-1)的表达分布及在DRG中过表达HO-1对神经病理性疼痛的作用。方法:构建保留性坐骨神经损伤(spared nerve injury,SNI)诱导的神经病理性疼痛模型;行为学检测机械性触诱发痛;免疫荧光染色检测DRG中HO-1在神经元中表达和分布;免疫印迹检测DRG中HO-1表达。结果:免疫荧光染色显示DRG中HO-1阳性神经元在SNI后数量显著减少;DRG中HO-1阳性神经元主要是IB4阳性的小型神经元(<300μm2);连续5天腹腔注射原卟啉IX氯化钴(cobalt protoporphyrin-IX,CoPP)能增加神经病理性疼痛小鼠的机械缩足阈值;鞘内注射过表达HO-1的腺病毒相关病毒(adenovirus associated virus,AAV)能特异性浸染DRG神经元,并上调HO-1表达;同时能有效提高神经病理性疼痛小鼠的机械缩足阈值,此效应持续21天以上。结论:DRG中HO-1主要表达在IB4阳性的小型神经元;过表达DRG神经元中HO-1能有效缓解SNI诱导的神经病理性疼痛。     

Attenuation of mechanical allodynia by clinically utilized drugs in a rat chemotherapy-induced neuropathic pain model

Chemotherapy-induced peripheral neuropathy is a common, dose-limiting side effect of cancer chemotherapeutic agents, including the vinca alkaloids such as vincristine. The resulting symptoms, which frequently include moderate to severe pain, can often be disabling. The current study utilized a vincristine-induced neuropathic pain animal model [Pain 93 (2001) 69], in which rats were surgically implanted with mini-osmotic pumps set to deliver vincristine sulfate (30 microg kg(-1)day(-1), i.v.), to examine the time course of progression of various pain modalities and to compare the dose-response effects of clinically utilized drugs on mechanical allodynia to further validate the relevance of this model to clinical pathology. Vincristine infusion resulted in significant cold allodynia after 1 week post-infusion, however mechanical and thermal nociception showed little to no effect. In contrast, marked mechanical allodynia occurred by 1 week of vincristine infusion and returned nearly to pre-infusion levels by the 4th week after infusion pump implantation. ED(50) values (micromol/kg, p.o.) were determined in the mechanical allodynia assay for lamotrigine (82), dextromethorphan (94), gabapentin (400), acetaminophen (1100) and carbamazepine (3600); however, aspirin and ibuprofen had no effects up to 300 and 1000 micromol/kg, respectively. Additionally, ED(50) values (micromol/kg, i.p.) were determined in the mechanical allodynia assay for clonidine (0.35) and morphine (0.62), but desipramine and celecoxib had no effects up to 66 and 260 micromol/kg, respectively. Findings from the current, preclinical study further validate this model as clinically relevant for chemotherapy-induced pain. The surprisingly good effects observed with acetaminophen warrant further investigation of its mechanism(s) of action in neuropathic pain.     

Effects of the novel analgesic,cizolirtine, in a rat model of neuropathic pain

Cizolirtine (5-9[(N,N-dimethylaminoethoxy)phenyl]methyl0-1-methyl-1H-pyrazol citrate) is a centrally acting analgesic with a currently unknown mechanism of action, whose efficacy has been demonstrated in various models of acute and inflammatory pain in rodents. Further studies were performed in order to assess its potential antinociceptive action in a well-validated model of neuropathic pain, i.e. that produced by unilateral sciatic nerve constriction in rats. Animals were subjected to relevant behavioural tests based on mechanical (vocalization threshold to paw pressure) and thermal (struggle latency to paw immersion in a cold (10 degrees C) water bath) stimuli, 2 weeks after sciatic nerve constriction, when pain-related behaviour was fully developed. Acute pretreatment with 2.5-10 mg/kg p.o. of cizolirtine reversed both mechanical and thermal allodynia. These effects were antagonized by prior injection of the alpha(2)-adrenoceptor antagonist idazoxan (0.5 mg/kg i.v.), but not the opioid receptor antagonist naloxone (0.1 mg/kg i.v.). On the other hand, cizolirtine (10 mg/kg p.o.) produced no motor deficits in animals using the rotarod test. Our study showed that cizolirtine suppressed pain-related behavioural responses to mechanical and cold stimuli in neuropathic rats, probably via an alpha(2)-adrenoceptor-dependent mechanism. These results suggest that cizolirtine may be useful for alleviating some neuropathic somatosensory disorders, in particular cold allodynia, with a reduced risk of undesirable side effects.     

Comparative activity of the anti-convulsants oxcarbazepine, carbamazepine, lamotrigine and gabapentin in a model of neuropathic pain in the rat and guinea-pig

Anti-epileptic drugs (AEDs) are increasingly used for the treatment of neuropathic pain. Oxcarbazepine is a recently introduced AED that is effective in treating epilepsy and has an improved side-effect profile compared to existing therapies. Here we have examined the effect of oxcarbazepine and other AEDs in a model of neuropathic pain in the rat and guinea-pig. Oxcarbazepine and carbamazepine (3-100 mg x kg(-1)) did not affect mechanical hyperalgesia or tactile allodynia induced by partial sciatic nerve ligation in the rat following oral administration. However, in the same model in the guinea-pig, both drugs produced up to 90% reversal of mechanical hyperalgesia with respective D(50) values of 10.7 and 0.8 mg x kg(-1). The active human metabolite of oxcarbazepine, monohydroxy derivative, was similarly active against mechanical hyperalgesia in the guinea-pig but not the rat. Lamotrigine (3-100 mg x kg(-1), p.o.) was effective against mechanical hyperlagesia in both species although it showed greater efficacy and potency in the guinea-pig (D(50) 4.7 mg x kg(-1)) compared to the rat (D(50) 27 mg kg(-1)). Lamotrigine produced slight inhibition of tactile allodynia in the rat only at the highest dose tested of 100 mg x kg(-1). Gabapentin was poorly active against mechanical hyperalgesia in both the rat and guinea-pig following a single oral administration (100 mg x kg(-1)), although upon repeated administration it produced up to 70 and 90% reversal in rat and guinea-pig, respectively. Gabapentin did however produce significant dose-related reversal of tactile allodynia in the rat following a single administration. These data show that oxcarbazepine and other AEDs are effective anti-hyperalgesic or anti-allodynic agents in an animal model of neuropathic pain, and provide further support for their use in the treatment of neuropathic pain in the clinic.     

Low doses of dextromethorphan have a beneficial effect in the treatment of neuropathic pain

N‐methyl‐D‐aspartate receptor (NMDAR) antagonists may be given in persistent neuropathic pain, but adverse events especially with ketamine may limit their clinical use. Less central and cognitive adverse events are described with dextromethorphan and memantine. These molecules have been explored in many preclinical and clinical studies, but data are conflicting as regards neuropathic pain alleviation. Dextromethorphan and memantine have been administered to animals after spinal nerve ligation (SNL) to evaluate their antinociceptive/cognitive effects and associated molecular events, including the phosphorylation of several tyrosine (pTyr¹³³⁶, pTyr¹⁴⁷²) residues in the NR2B NMDAR subunit. Spinal nerve ligation and sham animals received dextromethorphan (10 mg/kg, i.p.), memantine (20 mg/kg, i.p.) or saline (1 mL/kg, i.p.). These drugs were administered once symptoms of allodynia and hyperalgesia had developed. Tests were carried out before and after surgery. Tactile allodynia, mechanical hyperalgesia and spatial memory were, respectively, evaluated by von Frey, Randall & Selitto and Y‐maze tests and molecular events by Western blot analysis. Spinal nerve‐ligated animals displayed nociception and impaired spatial memory. Dextromethorphan, but not memantine, reversed neuropathic pain (NP) symptoms, restored spatial memory integrity and decreased the expression of pTyr¹³³⁶NR2B. Following postoperative administration of dextromethorphan, this study has demonstrated for the first time a concordance between behaviour, cognitive function and molecular events via pTyr¹³³⁶NR2B for neuropathic pain alleviation. Confirmation of these findings in patients would constitute a major step forward in the treatment of neuropathic pain and in the improvement of cognitive function and quality of life.     

Evidence for the involvement of the serotonergic, noradrenergic, and dopaminergic systems in the antidepressant-like action of riparin III obtained from Aniba riparia (Nees) Mez (Lauraceae) in mice

Previous work has shown that intraperitoneal administration of riparin III (ripIII) reduces immobility time in the forced swimming test (FST), which suggests potential antidepressant activity. As the mechanism of action is not completely understood, this study is aimed at investigating the antidepressant‐like action of ripIII. Following intraperitoneal administration of ripIII at doses of 25 and 50 mg/kg, there were decreases in the immobility time in the FST and tail suspension test without accompanying changes in ambulation (data not shown). The pretreatment of mice with sulpiride (50 mg/kg, i.p.), prazosin (1 mg/kg, i.p.), yohimbine (1 mg/kg, i.p.), and p‐chlorophenylalanine (PCPA, 100 mg/kg, i.p. for, four consecutive days) significantly prevented the anti‐immobility effect of ripIII in the FST. On the other hand, the anti‐immobility effect of ripIII (50 mg/kg, v.o.) was not altered by pretreatment of mice with SCH23390 (15 μg/kg, i.p.) Furthermore, ripIII potentiated the sleeping latency and sleeping time of the pentobarbital‐induced sleeping time test and also potentiated apomorphine (16 mg/kg, i.p.)‐induced hypothermia in mice. In conclusion, the present study provides evidence that the antidepressant‐like effect of ripIII is dependent on its interaction with the serotonergic, noradrenergic (α₁‐ and α₂‐ receptors), and dopaminergic (dopamine D₂ receptors) systems.     

Amelioration of neuropathic pain by novel transient receptor potential vanilloid 1 antagonist AS1928370 in rats without hyperthermic effect

Transient receptor potential vanilloid 1 (TRPV1) is activated by a variety of stimulations, such as endogenous ligands and low pH, and is believed to play a role in pain transmission. TRPV1 antagonists have been reported to be effective in several animal pain models; however, some compounds induce hyperthermia in animals and humans. We discovered the novel TRPV1 antagonist (R)-N-(1-methyl-2-oxo-1,2,3,4-tetrahydro-7-quinolyl)-2-[(2-methylpyrrolidin-1-yl)methyl]biphenyl-4-carboxamide (AS1928370) in our laboratory. AS1928370 bound to the resiniferatoxin-binding site on TRPV1 and inhibited capsaicin-mediated inward currents with an IC?? value of 32.5 nM. Although AS1928370 inhibited the capsaicin-induced Ca2(+) flux in human and rat TRPV1-expressing cells, the inhibitory effect on proton-induced Ca2(+) flux was extremely small. In addition, AS1928370 showed no inhibitory effects on transient receptor potential vanilloid 4, transient receptor potential ankyrin 1, and transient receptor potential melastatin 8 in concentrations up to 10 μM. AS1928370 improved capsaicin-induced secondary hyperalgesia and mechanical allodynia in an L5/L6 spinal nerve ligation model in rats with respective ED?? values of 0.17 and 0.26 mg/kg p.o. Furthermore, AS1928370 alleviated inflammatory pain in a complete Freund's adjuvant model at 10 mg/kg p.o. AS1928370 had no effect on rectal body temperature up to 10 mg/kg p.o., although a significant hypothermic effect was noted at 30 mg/kg p.o. In addition, AS1928370 showed no significant effect on motor coordination. These results suggest that blockage of the TRPV1 receptor without affecting the proton-mediated TRPV1 activation is a promising approach to treating neuropathic pain because of the potential wide safety margin against hyperthermic effects. As such, compounds such as ASP1928370 may have potential as new analgesic agents for treating neuropathic pain.     

Inhibition of paclitaxel-induced A-fiber hypersensitization by gabapentin

Paclitaxel (Taxol) is a widely used chemotherapeutic agent in the treatment of several tumors. However, its use is often associated with the generation of peripheral neuropathic pain expressed as mechanical allodynia and thermal hyperalgesia. The molecular mechanism behind this debilitating side effect is obscure, and efficient drugs for its prevention are required. We sought to clarify the cellular changes in the involved nociceptor types underlying paclitaxel-induced neuropathic pain and to test for an alleviating effect of gabapentin treatment in a murine model of paclitaxel-induced neuropathic pain. We found that a single treatment with paclitaxel (4 mg/kg i.p.) led to a decrease in both thermal and mechanical nociceptive thresholds as well as a reduction in the thresholds for 250-Hz (A delta-fiber) and 2000 Hz (A beta-fiber) but not 5-Hz (C-fiber) sine wave electrical stimuli-induced paw withdrawal. The paclitaxel-induced neuropathic pain was completely abrogated by gabapentin (30 mg/kg i.p.) treatment. Furthermore, we found that mRNA and protein levels of the voltage-gated calcium channel (alpha 2)delta-1 subunit (Ca(alpha 2)delta-1), one of the putative targets for gabapentin, was up-regulated in dorsal root ganglions (DRGs), as well as increased expression of Ca(alpha 2)delta-1 protein in medium/large-sized DRG neurons by immunohistochemistry, following paclitaxel treatment. This suggests that paclitaxel induces A-fiber-specific hypersensitization, which may contribute to the functional mechanical allodynia and hyperalgesia, and that gabapentin could be a potential therapeutic agent for paclitaxel-induced neuropathic pain.