am-1241 and Neuralgia

Influence of a relatively specific inhibitor cyclooxygenase (COX)-2, celecoxib, a relatively specific inhibitor of neuronal nitric oxide synthase (NOS), 7-Ni, and a relatively selective inhibitor of inducible NOS, L-NIL, on the action of a preferentially selective CB1 cannabinoid receptor agonist, Met-F-AEA and a selective CB2 cannabinoid receptor agonist, AM 1241 was investigated, in a streptozotocin (STZ)-induced neuropathy.. Studies were performed on male Wistar rats. Changes in nociceptive thresholds were determined using mechanical stimuli - the modification of the classic paw withdrawal test described by Randall-Selitto. Diabetes was induced by a single administration of STZ.. In a diabetic neuropathic pain model, pretreatment with celecoxib, L-NIL and 7-Ni, significantly increased the antihyperalgesic activity of both Met-F-AEA and AM 1241.. The results of this study seemed to indicate that the interaction between cannabinoid, COX-2 and NOS(s) systems might exist. Concomitant administration of small doses of CB1 and/or CB2 receptor agonists and COX-2 or NOS inhibitors can be effective in the alleviation of diabetic neuropathic pain.

Topics: Animals; Arachidonic Acids; Cannabinoids; Celecoxib; Cyclooxygenase Inhibitors; Diabetic Neuropathies; Drug Synergism; Hyperalgesia; Indazoles; Lysine; Male; Neuralgia; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type II; Pain Measurement; Rats; Rats, Wistar; Streptozocin

Cannabinoid CB₂ receptor activation by selective agonists has been shown to produce analgesic effects in preclinical models of inflammatory and neuropathic pain. However, mechanisms underlying CB₂-mediated analgesic effects remain largely unknown. The present study was conducted to elucidate the CB₂ receptor expression in 'pain relevant' tissues and the potential sites of action of CB₂ agonism in rats.. Expression of cannabinoid receptor mRNA was evaluated by quantitative RT-PCR in dorsal root ganglia (DRGs), spinal cords, paws and several brain regions of sham, chronic inflammatory pain (CFA) and neuropathic pain (spinal nerve ligation, SNL) rats. The sites of CB₂ mediated antinociception were evaluated in vivo following intra-DRG, intrathecal (i.t.) or intraplantar (i.paw) administration of potent CB₂-selective agonists A-836339 and AM1241.. CB₂ receptor gene expression was significantly up-regulated in DRGs (SNL and CFA), spinal cords (SNL) or paws (CFA) ipsilateral to injury under inflammatory and neuropathic pain conditions. Systemic A-836339 and AM1241 produced dose-dependent efficacy in both inflammatory and neuropathic pain models. Local administration of CB₂ agonists also produced significant analgesic effects in SNL (intra-DRG and i.t.) and CFA (intra-DRG) pain models. In contrast to A-836339, i.paw administration of AM-1241 dose-relatedly reversed the CFA-induced thermal hyperalgesia, suggesting that different mechanisms may be contributing to its in vivo properties.. These results demonstrate that both DRG and spinal cord are important sites contributing to CB₂ receptor-mediated analgesia and that the changes in CB₂ receptor expression play a crucial role for the sites of action in regulating pain perception.

Topics: Analgesia; Analgesics; Animals; Brain; Cannabinoids; Disease Models, Animal; Ganglia, Spinal; Inflammation; Male; Neuralgia; Opioid Peptides; Pain; Pain Perception; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB2; RNA, Messenger; Spinal Cord; Thiazoles

Topics: Animals; Cannabinoids; Disease Models, Animal; Male; Neuralgia; Receptor, Cannabinoid, CB2; Self Medication

Drug self-administration methods were used to test the hypothesis that rats would self-medicate with a cannabinoid CB(2) agonist to attenuate a neuropathic pain state. Self-medication of the CB(2) agonist (R,S)-AM1241, but not vehicle, attenuated mechanical hypersensitivity produced by spared nerve injury. Switching rats from (R,S)-AM1241 to vehicle self-administration also decreased lever responding in an extinction paradigm. (R,S)-AM1241 self-administration did not alter paw withdrawal thresholds in sham-operated or naive animals. The percentage of active lever responding was similar in naive groups self-administering vehicle or (R,S)-AM1241. The CB(2) antagonist SR144528 blocked both antiallodynic effects of (R,S)-AM1241 self-medication and the percentage of active lever responding in neuropathic (but not naive) rats. Neuropathic and sham groups exhibited similar percentages of active lever responding for (R,S)-AM1241 on a fixed ratio 1 (FR1) schedule. However, neuropathic animals worked harder than shams to obtain (R,S)-AM1241 when the schedule of reinforcement was increased (to FR6). (R,S)-AM1241 self-medication on FR1, FR3, or FR6 schedules attenuated nerve injury-induced mechanical allodynia. (R,S)-AM1241 (900μg intravenously) failed to produce motor ataxia observed after administration of the mixed CB(1)/CB(2) agonist WIN55,212-2 (0.5mg/kg intravenously). Our results suggest that cannabinoid CB(2) agonists may be exploited to treat neuropathic pain with limited drug abuse liability and central nervous system side effects. These studies validate the use of drug self-administration methods for identifying nonpsychotropic analgesics possessing limited abuse potential. These methods offer potential to elucidate novel analgesics that suppress spontaneous neuropathic pain that is not measured by traditional assessments of evoked pain.

Topics: Animals; Cannabinoids; Conditioning, Operant; Disease Models, Animal; Male; Neuralgia; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB2; Self Medication

There is growing interest in using cannabinoid receptor 2 (CB2) agonists for the treatment of neuropathic pain. We have synthesized a novel series of N-alkyl isatin acylhydrazone derivatives and have identified and characterized several of them as novel analogues with high functional activity and selectivity at human CB2 receptors using [(35)S]GTP-gamma-S assays. Binding affinities at human CB2 and CB1 were determined for compounds 28, 33, 40, 48, and 58. Structure-activity relationship studies of this novel series led to optimization of our lead compound, compound 33 (MDA19). Compound 33 possessed potent antiallodynic effects in a rat model of neuropathic pain but did not affect rat locomotor activity. More potent and more CB2-receptor-selective compounds, including compounds 37, 40, and 48, were also discovered.

Topics: Animals; CHO Cells; Cricetinae; Cricetulus; Drug Design; Humans; Hydrazones; Isatin; Neuralgia; Rats; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Structure-Activity Relationship; X-Ray Diffraction

Activation of cannabinoid CB(2) receptors suppresses neuropathic pain induced by traumatic nerve injury. The present studies were conducted to evaluate the efficacy of cannabinoid CB(2) receptor activation in suppressing painful peripheral neuropathy evoked by chemotherapeutic treatment with the antitumor agent paclitaxel. Rats received paclitaxel (2 mg/kg i.p./day) on 4 alternate days to induce mechanical hypersensitivity (mechanical allodynia). Mechanical allodynia was defined as a lowering of the threshold for paw withdrawal to stimulation of the plantar hind paw surface with an electronic von Frey stimulator. Mechanical allodynia developed in paclitaxel-treated animals relative to groups receiving the Cremophor EL/ethanol/saline vehicle at the same times. Two structurally distinct cannabinoid CB(2) agonists, the aminoalkylindole (R,S)-AM1241 [(R,S)-(2-iodo-5-nitrophenyl)-[1-((1-methyl-piperidin-2-yl)methyl)-1H-indol-3-yl]-methanone] and the cannabilactone AM1714 (1,9-dihydroxy-3-(1',1'-dimethylheptyl)-6H-benzo[c]chromene-6-one), produced a dose-related suppression of established paclitaxel-evoked mechanical allodynia after systemic administration. Pretreatment with the CB(2) antagonist SR144528 [5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-N-(1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)-1H-pyrazole-3-carboxamide], but not the CB(1) antagonist SR141716 [5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide], blocked the antiallodynic effects of both (R,S)-AM1241 and AM1714. Moreover, (R)-AM1241, but not (S)-AM1241, suppressed paclitaxel-evoked mechanical allodynia relative to either vehicle treatment or preinjection thresholds, consistent with mediation by CB(2). Administration of either the CB(1) or CB(2) antagonist alone failed to alter paclitaxel-evoked mechanical allodynia. Moreover, (R,S)-AM1241 did not alter paw withdrawal thresholds in rats that received the Cremophor EL vehicle in lieu of paclitaxel, whereas AM1714 induced a modest antinociceptive effect. Our data suggest that cannabinoid CB(2) receptors may be important therapeutic targets for the treatment of chemotherapy-evoked neuropathy.

Topics: Animals; Antineoplastic Agents, Phytogenic; Cannabinoids; Chromones; Dimethyl Sulfoxide; Male; Morphine; Neuralgia; Paclitaxel; Pain Threshold; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB2; Stereoisomerism

The ability of cannabinoids to suppress mechanical hypersensitivity (mechanical allodynia) induced by treatment with the chemotherapeutic agent vincristine was evaluated in rats. Sites of action were subsequently identified.. Mechanical hypersensitivity developed over the course of ten daily injections of vincristine relative to groups receiving saline at the same times. Effects of the CB1/CB2 receptor agonist WIN55,212-2, the receptor-inactive enantiomer WIN55,212-3, the CB2-selective agonist (R,S)-AM1241, the opiate agonist morphine and vehicle on chemotherapy-induced neuropathy were evaluated. WIN55,212-2 was administered intrathecally (i.t.) or locally in the hindpaw to identify sites of action. Pharmacological specificity was established using competitive antagonists for CB1 (SR141716) or CB2 receptors (SR144528).. Systemic administration of WIN55,212-2, but not WIN55,212-3, suppressed vincristine-evoked mechanical allodynia. A leftward shift in the dose-response curve was observed following WIN55,212-2 relative to morphine treatment. The CB1 (SR141716) and CB2 (SR144528) antagonists blocked the anti-allodynic effects of WIN55,212-2. (R,S)-AM1241 suppressed vincristine-induced mechanical hypersensitivity through a CB2 mechanism. Both cannabinoid agonists suppressed vincristine-induced mechanical hypersensitivity without inducing catalepsy. Spinal sites of action are implicated in cannabinoid modulation of chemotherapy-induced neuropathy. WIN55,212-2, but not WIN55,212-3, administered i.t. suppressed vincristine-evoked mechanical hypersensitivity at doses that were inactive following local hindpaw administration. Spinal coadministration of both the CB1 and CB2 antagonists blocked the anti-allodynic effects of WIN55,212-2.. Cannabinoids suppress the maintenance of vincristine-induced mechanical allodynia through activation of CB1 and CB2 receptors. These anti-allodynic effects are mediated, at least in part, at the level of the spinal cord.

Topics: Animals; Benzoxazines; Body Weight; Camphanes; Cannabinoids; Catalepsy; Dose-Response Relationship, Drug; Hindlimb; Hyperesthesia; Injections, Intraperitoneal; Injections, Spinal; Male; Morphine; Morpholines; Naphthalenes; Neuralgia; Pain Measurement; Pain Threshold; Physical Stimulation; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Rimonabant; Thermosensing; Vincristine