3-(2-hydroxy-4-(1-1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol has been researched along with Pain* in 25 studies
1 review(s) available for 3-(2-hydroxy-4-(1-1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol and Pain
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The synthetic CB
More than 500 molecules have been identified as components of Cannabis sativa (C. sativa), of which the most studied is Δ Topics: Analgesics; Animals; Anti-Anxiety Agents; Cannabinoid Receptor Agonists; Cannabinoids; Controlled Substances; Cyclohexanols; Dronabinol; Humans; Mental Disorders; Pain; Phenanthridines; Receptor, Cannabinoid, CB1 | 2021 |
24 other study(ies) available for 3-(2-hydroxy-4-(1-1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol and Pain
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Effects of morphine/CP55940 mixtures on an impulsive choice task in rhesus monkeys.
µ-Opioid receptor agonists are commonly used to treat pain despite their adverse effects. In preclinical studies, cannabinoid receptor agonists increase the potency of opioids for producing antinociceptive but not reinforcing effects. It is unknown whether other adverse effects of these drugs, such as impairment of complex behavior, are enhanced by their co-administration. This study characterized the effects of morphine (µ-opioid receptor agonist; 0.32-5.6 mg/kg, subcutaneously) and CP55940 (CB1/CB2 cannabinoid receptor agonist; 0.0032-0.32 mg/kg, subcutaneously), alone and in mixtures, in monkeys (n=3) choosing between one pellet delivered immediately and two pellets delivered after a delay. Two consecutive choices of the immediate or delayed reward decreased or increased, respectively, the delay. The median adjusted delay, indicating indifference between the immediate and delayed reinforcers, was increased by morphine (3.2 mg/kg) and CP55940 (0.01-0.032 mg/kg). Performance after administration of morphine (0.32 and 1 mg/kg)/CP55940 (0.0032-0.032 mg/kg) mixtures was not different from performance after CP55940 alone. Neither morphine, CP55940, nor mixtures decreased the median adjusted delay (i.e. increased impulsivity). These findings failed to confirm previous studies showing that morphine increases impulsivity, perhaps because of procedural differences among studies. Treatment of pain often requires repeated drug administration; thus, it remains to be determined whether the present findings predict the effects of chronically administered morphine/CP5540 mixtures on impulsive choice. Topics: Analgesics, Opioid; Animals; Cannabinoid Receptor Agonists; Choice Behavior; Cyclohexanols; Dose-Response Relationship, Drug; Impulsive Behavior; Macaca mulatta; Male; Morphine; Pain; Receptor, Cannabinoid, CB1; Receptors, Opioid, mu; Reinforcement, Psychology | 2018 |
Sex differences in antinociceptive response to Δ-9-tetrahydrocannabinol and CP 55,940 in the mouse formalin test.
Cannabinoids have shown promise for the treatment of intractable pain states and may represent an alternative pharmacotherapy for pain management. A growing body of clinical evidence suggests a role for sex in pain perception and in cannabinoid response. We examined cannabinoid sensitivity and tolerance in male and female mice expressing a desensitization-resistant form (S426A/S430A) of the cannabinoid type 1 receptor (CB1R). Mice were assessed for acute and inflammatory nociceptive behaviors in the formalin test following pretreatment with either vehicle or mixed CB1R/CB2R agonists, Δ-9-tetrahydrocannabinol ([INCREMENT]-THC) (1-6 mg/kg) or CP 55,940 (0.06-0.2 mg/kg). Tolerance to the effects of 6 mg/kg [INCREMENT]-THC or 0.1 mg/kg CP 55,940 was examined by the formalin test following chronic daily dosing. Female mice showed decreased sensitivity to the effects of [INCREMENT]-THC and CP 55,940 compared with male mice. The S426A/S430A mutation increased the attenuation of nociceptive behaviors for both agonists in both sexes. Female mice displayed delayed tolerance to [INCREMENT]-THC compared with male mice, whereas the S426A/S430A mutation conferred a delay in tolerance to [INCREMENT]-THC in both sexes. Male S426A/S430A mutant mice also display resistance to tolerance to CP 55,940 compared with wild-type controls. This study demonstrates sex and genotype differences in response for two different cannabinoid agonists. The results underscore the importance of including both male and female mice in preclinical studies of pain and cannabinoid pharmacology. Topics: Analgesics; Analysis of Variance; Animals; Cyclohexanols; Disease Models, Animal; Dose-Response Relationship, Drug; Dronabinol; Drug Tolerance; Female; Formaldehyde; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Pain; Pain Measurement; Receptor, Cannabinoid, CB1; Sex Characteristics; Time Factors; Treatment Outcome | 2018 |
Quantification of pain in sickle mice using facial expressions and body measurements.
Pain is a hallmark feature of sickle cell disease (SCD). Subjects typically quantify pain by themselves, which can be biased by other factors leading to overtreatment or under-treatment. Reliable and accurate quantification of pain, in real time, might enable to provide appropriate levels of analgesic treatment. The mouse grimace scale (MGS), a standardized behavioral coding system with high accuracy and reliability has been used to quantify varied types of pain. We hypothesized that addition of the objective parameters of body length and back curvature will strengthen the reproducibility of MGS. We examined MGS scores and body length and back curvature of transgenic BERK sickle and control mice following cold treatment or following treatment with analgesic cannabinoid CP55,940. We observed that sickle mice demonstrated decreased length and increased back curvature in response to cold. These observations correlate with changes in facial expression for the MGS score. CP55,940 treatment of sickle mice showed an increase in body length and a decrease in back curvature concordant with MGS scores indicative of an analgesic effect. Thus, body parameters combined with facial expressions may provide a quantifiable unbiased method for objective measure of pain in SCD. Topics: Analgesics; Anemia, Sickle Cell; Animals; Behavior, Animal; Cold Temperature; Cyclohexanols; Disease Models, Animal; Facial Expression; Female; Humans; Male; Mice; Mice, Transgenic; Pain; Pain Measurement; Posture; Reproducibility of Results; Research Design | 2016 |
Mouse models for studying pain in sickle disease: effects of strain, age, and acuteness.
The clinical management of severe pain associated with sickle cell disease (SCD) remains challenging. Development of an optimal therapy would be facilitated by use of murine model(s) with varying degrees of sickling and pain tests that are most sensitive to vaso-occlusion. We found that young (≤3 months old) NY1DD and S+S(Antilles) mice (having modest and moderate sickle phenotype, respectively) exhibited evidence of deep tissue/musculoskeletal pain. Deep tissue pain and cold sensitivity in S+S(Antilles) mice increased significantly with both age and incitement of hypoxia/reoxygenation (H/R). C57/BL6 mice (genetic background strain of NY1DD and S+S(Antilles) ) were hypersensitive to mechanical and heat stimuli, even without the sickle transgene. H/R treatment of HbSS-BERK mice with severe sickle phenotype resulted in significantly decreased withdrawal thresholds and enhanced mechanical, thermal and deep tissue hyperalgesia. Deep hyperalgesia incited by H/R in HbSS-BERK was ameliorated by CP 55940, a cannabinoid receptor agonist. Thus, assessment of deep tissue pain appears to be the most sensitive measure for studying pain mechanisms across mouse models of SCD, and HbSS-BERK mice may be the best model for vaso-occlusive and chronic pain of SCD. Topics: Age Factors; Analgesics; Anemia, Sickle Cell; Animals; Cannabinoid Receptor Antagonists; Cyclohexanols; Disease Models, Animal; Humans; Hyperalgesia; Hypoxia; Mice; Mice, Inbred C57BL; Mice, Transgenic; Pain; Pain Measurement; Temperature | 2012 |
Effects of alterations in cannabinoid signaling, alone and in combination with morphine, on pain-elicited and pain-suppressed behavior in mice.
Inhibitors of fatty acid amide hydrolase (FAAH) and anandamide (AEA) uptake, which limit the degradation of endogenous cannabinoids, have received interest as potential therapeutics for pain. There is also evidence that endogenous cannabinoids mediate the antinociceptive effects of opioids. Assays of pain-elicited and pain-suppressed behavior have been used to differentiate the effects of drugs that specifically alter nociception from drugs that alter nociception caused by nonspecific effects such as catalepsy or a general suppression of activity. Using such procedures, this study examines the effects of the direct cannabinoid type 1 (CB1) agonist (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol (CP55940), the FAAH inhibitor cyclohexylcarbamic acid 3'-carbamoylbiphenyl-3-yl ester (URB597), and the AEA uptake inhibitor N-(4-hydroxyphenyl) arachidonylamide (AM404). Additional experiments examined these compounds in combination with morphine. CP55940 produced antinociception in assays of pain-elicited, but not pain-suppressed, behavior and disrupted responding in an assay of schedule-controlled behavior. URB597 and AM404 produced antinociception in assays of pain-elicited and pain-suppressed behavior in which acetic acid was the noxious stimulus, but had no effect on the hotplate and schedule-controlled responding. CP55940 in combination with morphine resulted in effects greater than those of morphine alone in assays of pain-elicited and scheduled-controlled behavior but not pain-suppressed behavior. URB597 in combination with morphine resulted in enhanced morphine effects in assays of pain-elicited and pain-suppressed behavior in which diluted acetic acid was the noxious stimulus, but did not alter morphine's effects on the hotplate or schedule-controlled responding. These studies suggest that, compared with direct CB1 agonists, manipulations of endogenous cannabinoid signaling have enhanced clinical potential; however, their effects depend on the type of noxious stimulus. Topics: Amidohydrolases; Analgesics; Animals; Arachidonic Acids; Benzamides; Cannabinoid Receptor Modulators; Carbamates; Cyclohexanols; Endocannabinoids; Male; Mice; Mice, Inbred C57BL; Morphine; Nociception; Pain; Polyunsaturated Alkamides; Receptor, Cannabinoid, CB1 | 2012 |
Dissociable effects of the cannabinoid receptor agonists Δ9-tetrahydrocannabinol and CP55940 on pain-stimulated versus pain-depressed behavior in rats.
Cannabinoid receptor agonists produce reliable antinociception in most preclinical pain assays but have inconsistent analgesic efficacy in humans. This disparity suggests that conventional preclinical assays of nociception are not sufficient for the prediction of cannabinoid effects related to clinical analgesia. To extend the range of preclinical cannabinoid assessment, this study compared the effects of the marijuana constituent and low-efficacy cannabinoid agonist Δ9-tetrahydrocannabinol (THC) and the high-efficacy synthetic cannabinoid agonist 3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol (CP55940) in assays of pain-stimulated and pain-depressed behavior. Intraperitoneal injection of dilute lactic acid (1.8% in 1 ml/kg) stimulated a stretching response or depressed intracranial self-stimulation (ICSS) in separate groups of male Sprague-Dawley rats. THC (0.1-10 mg/kg) and CP55940 (0.0032-0.32 mg/kg) dose-dependently blocked acid- stimulated stretching but only exacerbated acid-induced depression of ICSS at doses that also decreased control ICSS in the absence of a noxious stimulus. Repeated THC produced tolerance to sedative rate-decreasing effects of THC on control ICSS in the absence of the noxious stimulus but failed to unmask antinociception in the presence of the noxious stimulus. THC and CP55940 also failed to block pain-related depression of feeding in rats, although THC did attenuate satiation-related depression of feeding. In contrast to the effects of the cannabinoid agonists, the clinically effective analgesic and nonsteroidal anti-inflammatory drug ketoprofen (1 mg/kg) blocked acid-stimulated stretching and acid-induced depression of both ICSS and feeding. The poor efficacy of THC and CP55940 to block acute pain-related depression of behavior in rats agrees with the poor efficacy of cannabinoids to treat acute pain in humans. Topics: Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Behavior, Animal; Brain; Cannabinoid Receptor Agonists; Conditioning, Operant; Cyclohexanols; Dose-Response Relationship, Drug; Dronabinol; Eating; Electrodes, Implanted; Ketoprofen; Lactic Acid; Male; Pain; Rats; Rats, Sprague-Dawley; Self Stimulation | 2012 |
Attenuation of morphine antinociceptive tolerance by a CB(1) receptor agonist and an NMDA receptor antagonist: Interactive effects.
CB(1) cannabinoid (CB(1)) receptor agonists and N-Methyl-d-Aspartate (NMDA) receptor antagonists attenuate the development of morphine antinociceptive tolerance. The present study used dose-addition analysis to evaluate CB(1)/NMDA receptor interactions on this endpoint. Chronic morphine administration (5 days, 100 mg/kg, twice daily) resulted in a 2.8-fold rightward shift in the morphine dose-effect curve. Co-administration of either the CB(1) receptor agonist CP-55940 (5-(1,1-Dimethylheptyl)-2-[5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]phenol; 0.32-1.0 mg/kg) or the NMDA receptor antagonist (-)-6-phosphonomethyl-deca-hydroisoquinoline-3-carboxylic acid (LY235959; 1.0-3.2 mg/kg) with morphine dose-dependently attenuated morphine tolerance. The relative potency of each drug alone was quantified using a defined level of effect (one-quarter log shift in the morphine dose-effect curve), resulting in equieffective doses of 0.42 mg/kg and 1.1 mg/kg for CP-55940 and LY235959, respectively. Subsequent experiments assessed CP-55940/LY235959 interactions using a fixed-proportion design. Co-administration of CP-55940/LY235959 mixtures (1:1, 1:3.2, or 1:10 CP-55940/LY235959) with morphine dose-dependently attenuated morphine tolerance. Isobolographic and dose-addition analysis were used to statistically compare the experimentally determined potency for each mixture (z(mix)) with predicted additive potency (z(add)). Mixtures of 1:1 and 1:3.2 CP-55940/LY235959 produced additive effects (z(add) = z(mix)), while the mixture of 1:10 CP-55940/LY235959 produced a supra-additive effect (z(add) > z(mix)). These results suggest that CP-55940 and LY235959 produce additive or supra-additive attenuation of morphine antinociceptive tolerance after repeated morphine administration, depending on their relative concentrations. Topics: Analgesics; Analgesics, Opioid; Animals; Cyclohexanols; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Drug Tolerance; Excitatory Amino Acid Antagonists; Hot Temperature; Isoquinolines; Male; Mice; Mice, Inbred C57BL; Morphine; Pain; Pain Measurement; Receptor, Cannabinoid, CB1; Receptors, N-Methyl-D-Aspartate | 2010 |
In vitro and in vivo pharmacological characterization of two novel selective cannabinoid CB(2) receptor inverse agonists.
We have previously developed quinolone-3-carboxamides with the aim of obtaining new ligands for both cannabinoid receptors, CB1 and CB2. Our preliminary screening led to the identification of cannabinoid receptor ligands characterized by high affinity and, in some cases, also selectivity for CB(2) receptors. Specifically, three compounds, 1, 2 and 3 showed high affinity for CB2 as well as high selectivity over CB1 receptors. In addition, the activity shown by 1 against the formalin-induced nocifensive response in mice, reported in our previous paper, suggests that quinolone-3-carboxamides possess anti-nociceptive properties. In the present work, we have performed functional in vitro bioassays with the aim of investigating the functional activity in the [35S]GTPgammaS binding assay of the other two compounds that, like 1, behave as CB2 selective ligands, and their potential analgesic actions in vivo. We found that both 2 and 3 behave in vitro as CB2 inverse agonists and are able to decrease nociceptive behaviour in the late phase of the formalin test only at the highest dose tested, although, at lower doses, they prevent the anti-nociceptive effects of a selective CB2 partial agonist in the formalin test. These results identify in 2 and 3 two novel, potent and selective CB2 antagonists/inverse agonists and confirm previous reports in the literature that, in addition to agonists at cannabinoid CB2 receptors, also inverse agonists/antagonists at these receptors show promise as anti-inflammatory agents. Topics: Analgesics; Animals; CHO Cells; Cricetinae; Cricetulus; Cyclohexanols; Drug Inverse Agonism; Formaldehyde; Guanosine 5'-O-(3-Thiotriphosphate); Mice; Molecular Structure; Pain; Quinolones; Radioligand Assay; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Structure-Activity Relationship | 2010 |
Pain-related behaviors and neurochemical alterations in mice expressing sickle hemoglobin: modulation by cannabinoids.
Sickle cell disease causes severe pain. We examined pain-related behaviors, correlative neurochemical changes, and analgesic effects of morphine and cannabinoids in transgenic mice expressing human sickle hemoglobin (HbS). Paw withdrawal threshold and withdrawal latency (to mechanical and thermal stimuli, respectively) and grip force were lower in homozygous and hemizygous Berkley mice (BERK and hBERK1, respectively) compared with control mice expressing human hemoglobin A (HbA-BERK), indicating deep/musculoskeletal and cutaneous hyperalgesia. Peripheral nerves and blood vessels were structurally altered in BERK and hBERK1 skin, with decreased expression of mu opioid receptor and increased calcitonin gene-related peptide and substance P immunoreactivity. Activators of neuropathic and inflammatory pain (p38 mitogen-activated protein kinase, STAT3, and mitogen-activated protein kinase/extracellular signal-regulated kinase) showed increased phosphorylation, with accompanying increase in COX-2, interleukin-6, and Toll-like receptor 4 in the spinal cord of hBERK1 compared with HbA-BERK. These neurochemical changes in the periphery and spinal cord may contribute to hyperalgesia in mice expressing HbS. In BERK and hBERK1, hyperalgesia was markedly attenuated by morphine and cannabinoid receptor agonist CP 55940. We show that mice expressing HbS exhibit characteristics of pain observed in sickle cell disease patients, and neurochemical changes suggestive of nociceptor and glial activation. Importantly, cannabinoids attenuate pain in mice expressing HbS. Topics: Anemia, Sickle Cell; Animals; Behavior, Animal; Calcitonin Gene-Related Peptide; Cannabinoid Receptor Agonists; Cannabinoids; Cyclohexanols; Disease Models, Animal; Female; Hemoglobin, Sickle; Humans; Hyperalgesia; Male; Mice; Mice, Knockout; Mice, Transgenic; Morphine; Neuroglia; Pain; Receptors, Opioid, mu; Recombinant Proteins; Skin; Spinal Cord; Substance P | 2010 |
Antinociceptive effects of the non-selective cannabinoid receptor agonist CP 55,940 are absent in CB1(-/-) and not CB2(-/-) mice in models of acute and persistent pain.
Previous studies have suggested a role for both CB1 and CB2 cannabinoid receptors in modulation of nociception. To further examine the role of CB1 and CB2 receptors in antinociception, we evaluated the efficacy of the non-selective cannabinoid receptor agonist, CP 55,940, in models of acute, inflammatory, and neuropathic pain in control mice, CB1 receptor knockout mice, and CB2 receptor knockout mice. In control C57BL/6 mice, administration of CP 55,940 (0.03-0.3 mg/kg, i.p.) reversed complete Freund's adjuvant-induced tactile allodynia, reversed tactile allodynia in the spinal nerve ligation model and inhibited the noxious heat-evoked tail withdrawal response. In addition to its antinociceptive effects, CP 55,940 produced an impairment of motor coordination in the rotarod test. The antinociceptive effects produced by CP 55,940 and associated motor deficits were found to be completely abolished in CB1 receptor knockout mice. In contrast, the antinociceptive effects of CP 55,940 in all pain models were fully retained in CB2 receptor knockout mice, along with the associated motor deficits. The results suggest that the antinociceptive effects of CP 55,940 in models of acute and persistent pain, along with the associated motor deficits, are mediated by CB1 receptors, and likely not CB2 receptors. Topics: Analgesics; Animals; Cyclohexanols; Disease Models, Animal; Dose-Response Relationship, Drug; Freund's Adjuvant; Hot Temperature; Mice; Mice, Inbred C57BL; Mice, Knockout; Motor Activity; Pain; Pain Measurement; Physical Stimulation; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Spinal Nerves | 2009 |
Evaluation of prevalent phytocannabinoids in the acetic acid model of visceral nociception.
Considerable preclinical research has demonstrated the efficacy of Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the primary psychoactive constituent of Cannabis sativa, in a wide variety of animal models of pain, but few studies have examined other phytocannabinoids. Indeed, other plant-derived cannabinoids, including cannabidiol (CBD), cannabinol (CBN), and cannabichromene (CBC) elicit antinociceptive effects in some assays. In contrast, tetrahydrocannabivarin (THCV), another component of cannabis, antagonizes the pharmacological effects of Delta(9)-THC. These results suggest that various constituents of this plant may interact in a complex manner to modulate pain. The primary purpose of the present study was to assess the antinociceptive effects of these other prevalent phytocannabinoids in the acetic acid stretching test, a rodent visceral pain model. Of the cannabinoid compounds tested, Delta(9)-THC and CBN bound to the CB(1) receptor and produced antinociceptive effects. The CB(1) receptor antagonist, rimonabant, but not the CB(2) receptor antagonist, SR144528, blocked the antinociceptive effects of both compounds. Although THCV bound to the CB(1) receptor with similar affinity as Delta(9)-THC, it had no effects when administered alone, but antagonized the antinociceptive effects of Delta(9)-THC when both drugs were given in combination. Importantly, the antinociceptive effects of Delta(9)-THC and CBN occurred at lower doses than those necessary to produce locomotor suppression, suggesting motor dysfunction did not account for the decreases in acetic acid-induced abdominal stretching. These data raise the intriguing possibility that other constituents of cannabis can be used to modify the pharmacological effects of Delta(9)-THC by either eliciting antinociceptive effects (i.e., CBN) or antagonizing (i.e., THCV) the actions of Delta(9)-THC. Topics: Acetic Acid; Analgesics; Animals; Anti-Obesity Agents; Camphanes; Cannabinoids; Cyclohexanols; Dose-Response Relationship, Drug; Dronabinol; Male; Mice; Mice, Inbred ICR; Motor Activity; Pain; Pain Measurement; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Rimonabant; RNA, Messenger | 2009 |
In vitro and in vivo characterization of A-796260: a selective cannabinoid CB2 receptor agonist exhibiting analgesic activity in rodent pain models.
Selective cannabinoid CB2 receptor agonists have demonstrated analgesic activity across multiple preclinical pain models. AM1241 is an indole derivative that exhibits high affinity and selectivity for the CB2 binding site and broad spectrum analgesic activity in rodent models, but is not an antagonist of CB2 in vitro functional assays. Additionally, its analgesic effects are mu-opioid receptor-dependent. Herein, we describe the in vitro and in vivo pharmacological properties of A-796260, a novel CB2 agonist.. A-796260 was characterized in radioligand binding and in vitro functional assays at rat and human CB1 and CB2 receptors. The behavioural profile of A-796260 was assessed in models of inflammatory, post-operative, neuropathic, and osteoarthritic (OA) pain, as well as its effects on motor activity. The receptor specificity was confirmed using selective CB1, CB2 and mu-opioid receptor antagonists.. A-796260 exhibited high affinity and agonist efficacy at human and rat CB2 receptors, and was selective for the CB2 vs CB1 subtype. Efficacy in models of inflammatory, post-operative, neuropathic and OA pain was demonstrated, and these activities were selectively blocked by CB2, but not CB1 or mu-opioid receptor-selective antagonists. Efficacy was achieved at doses that had no significant effects on motor activity.. These results further confirm the therapeutic potential of CB2 receptor-selective agonists for the treatment of pain. In addition, they demonstrate that A-796260 may be a useful new pharmacological compound for further studying CB2 receptor pharmacology and for evaluating its role in the modulation of pain. Topics: Analgesics, Non-Narcotic; Animals; Arthritis, Experimental; Cells, Cultured; Constriction, Pathologic; Cyclic AMP-Dependent Protein Kinases; Cyclohexanols; Cyclopropanes; Humans; Hyperalgesia; Immunosuppressive Agents; Joints; Male; Microscopy, Fluorescence; Morpholines; Motor Activity; Pain; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB2; Sciatica | 2008 |
Effect of CP55,940 on mechanosensory spinal neurons following chronic inflammation.
Cannabinoid receptor agonists have previously been shown to produce antinociceptive effects in rodent models of inflammatory pain. In the present study, we characterized responses of spinal dorsal horn neurons receiving sensory input from the hind paw in rats that had received intraplantar injection of complete Freund's adjuvant (CFA), and examined effects of the nonselective CB1/2 receptor agonist CP55,940 on spinal neuron responses. Systemic (i.v.) administration of CP55,940 failed to attenuate responses of dorsal horn neurons to noxious mechanical stimulation in naïve rats, but significantly reduced responses in CFA-inflamed rats to 25.78+/-13.7% of vehicle control at a cumulative dose of 0.8 mg/kg (ID50=0.28+/-0.02 mg/kg). Additionally, local administration of CP55,940 (10 microM) to the spinal cord reduced responses of mechanosensory dorsal horn neurons in CFA-inflamed rats to 67.15+/-7.1% of vehicle control. The inhibitory action of CP55,940 on spinal dorsal horn neurons in CFA-inflamed rats was mediated by CB1 receptors since local pretreatment with the CB1 receptor antagonist AM251 (10 microM) blocked this effect, while the CB2 receptor antagonist AM630 (10 microM) was ineffective. Our results suggest that following inflammation, the inhibition of spinal nociceptive transmission by CP55,940 is mediated in part by spinal CB1 receptors, and not spinal CB2 receptors. Topics: Afferent Pathways; Animals; Cannabinoid Receptor Modulators; Cannabinoids; Chronic Disease; Cyclohexanes; Cyclohexanols; Dose-Response Relationship, Drug; Inflammation; Male; Mechanoreceptors; Nociceptors; Pain; Phenols; Posterior Horn Cells; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Receptors, Cannabinoid | 2007 |
Synergistic and additive interactions of the cannabinoid agonist CP55,940 with mu opioid receptor and alpha2-adrenoceptor agonists in acute pain models in mice.
1. Cannabinoid receptor agonists elicit analgesic effects in acute and chronic pain states via spinal and supraspinal pathways. We investigated whether the combination of a cannabinoid agonist with other classes of antinociceptive drugs exerted supra-additive (synergistic) or additive effects in acute pain models in mice. 2. The interactions between the cannabinoid agonist CP55,940, alpha2-adrenoceptor agonist dexmedetomidine and mu-opioid receptor agonist morphine were evaluated by isobolographic analysis of antinociception in hot plate (55 degrees C) and tail flick assays in conscious male Swiss mice. Drug interactions were examined by administering fixed-ratio combinations of agonists (s.c.) in 1:1, 3:1 and 1:3 ratios of their respective ED50 fractions. 3. CP55,940, dexmedetomidine and morphine all caused dose-dependent antinociception. In the hot plate and tail flick assays, ED50 values (mg kg(-1)) were CP55,940 1.13 and 0.51, dexmedetomidine 0.066 and 0.023, and morphine 29.4 and 11.3, respectively. Synergistic interactions existed between CP55,940 and dexmedetomidine in the hot plate assay, and CP55,940 and morphine in both assays. Additive interactions were found for CP55,940 and dexmedetomidine in the tail flick assay, and dexmedetomidine and morphine in both assays. 4. Thus, an alpha2-adrenoceptor agonist or mu opioid receptor agonist when combined with a cannabinoid receptor agonist showed significant synergy in antinociception in the hot plate test. However, for the tail flick nociceptive response to heat, only cannabinoid and mu opioid receptor antinociceptive synergy was demonstrated. If these results translate to humans, then prudent selection of dose and receptor-specific agonists may allow an improved therapeutic separation from unwanted side effects. Topics: Acute Disease; Adrenergic alpha-Agonists; Analgesics; Analgesics, Non-Narcotic; Analgesics, Opioid; Animals; Cannabinoids; Cyclohexanols; Dexmedetomidine; Dose-Response Relationship, Drug; Drug Synergism; Injections, Spinal; Male; Mice; Morphine; Pain; Pain Measurement; Receptors, Opioid, mu | 2005 |
Pharmacological and pharmacokinetic characterization of the cannabinoid receptor 2 agonist, GW405833, utilizing rodent models of acute and chronic pain, anxiety, ataxia and catalepsy.
To date, two cannabinoid receptors have been identified, CB1 and CB2. Activation of these receptors with non-selective cannabinoid receptor agonists reduces pain sensitivity in animals and humans. However, activation of CB1 receptors is also associated with central side effects, including ataxia and catalepsy. More recently, a role for selective CB2 agonists in pain modification has been demonstrated. GW405833, a selective CB2 agonist, was recently reported to partially reverse the inflammation and hyperalgesia in a rat model of acute inflammation. In the current report, we extend the characterization and therapeutic potential of this compound. For the first time, we show that GW405833 selectively binds both rat and human CB2 receptors with high affinity, where it acts as a partial agonist (approximately 50% reduction of forskolin-mediated cAMP production compared to the full cannabinoid agonist, CP55,940). We also report for the first time that intraperitoneal administration of GW405833 (0.3-100 mg/kg) to rats shows linear, dose-dependent increases in plasma levels and substantial penetration into the central nervous system. In addition, GW405833 (up to 30 mg/kg) elicits potent and efficacious antihyperalgesic effects in rodent models of neuropathic, incisional and chronic inflammatory pain, the first description of this compound in these models. In contrast, analgesia, sedation and catalepsy were not observed in this dose range, but were apparent at 100 mg/kg. Additionally, GW405833 was not antihyperalgesic against chronic inflammatory pain in CB2 knockout mice. These data support the tenet that selective CB2 receptor agonists have the potential to treat pain without eliciting the centrally-mediated side effects associated with non-selective cannabinoid agonists, and highlight the utility of GW405833 for the investigation of CB2 physiology. Topics: Amines; Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Anxiety; Ataxia; Behavior, Animal; Benzoxazines; Binding, Competitive; Catalepsy; CHO Cells; Cricetinae; Cricetulus; Cyclic AMP; Cyclohexanecarboxylic Acids; Cyclohexanols; Disease Models, Animal; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Gabapentin; gamma-Aminobutyric Acid; Humans; Immunosuppressive Agents; Indoles; Indomethacin; Inflammation; Male; Mice; Mice, Knockout; Morpholines; Naphthalenes; Pain; Pain Measurement; Psychomotor Performance; Rats; Rats, Sprague-Dawley; Reaction Time; Receptor, Cannabinoid, CB2; Time Factors | 2005 |
Interaction between gamma-aminobutyric acid GABAB and cannabinoid CB1 receptors in spinal pain pathways in rat.
Antinociceptive effects of cannabinoids are mediated, in part, at the spinal level. Cannabinoid CB1 receptors are co-localized with dorsal horn interneurons containing gamma-aminobutyric acid (GABA). In this study, we investigated the interaction between intrathecally administered cannabinoid and GABA(B) receptor agonists and antagonists in the modulation of formalin-induced pain at the spinal level. Intrathecal pretreatment of rats with a cannabinoid receptor antagonist [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1-H-pyrazole-3-carboxamide] (SR141716A, 30 microg) decreased the analgesic effect of the intrathecal administration of the GABA(B) receptor agonist, baclofen (0.125 microg and 0.25 microg). Intrathecal administration of the GABA(B) receptor antagonist, saclofen (30 microg), 10 min before administration of the cannabinoid receptor agonist (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)-phenyl]-trans-4-(3-hydroxy-propyl)-cyclohexano (CP55940), did not affect the analgesia produced by the cannabinoid receptor agonist. Our results confirm that intrathecal administration of cannabinoid and GABA(B) receptor agonists have analgesic effects and that spinal antinociceptive effects of GABA(B) receptor agonists are likely through endocannabinoid modulation. Topics: Analysis of Variance; Animals; Baclofen; Cyclohexanols; Dose-Response Relationship, Drug; Drug Interactions; Formaldehyde; GABA Agonists; GABA Antagonists; GABA-B Receptor Agonists; GABA-B Receptor Antagonists; Injections, Spinal; Male; Pain; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptors, GABA-B; Rimonabant; Signal Transduction; Spinal Cord | 2005 |
Antihyperalgesic properties of the cannabinoid CT-3 in chronic neuropathic and inflammatory pain states in the rat.
CT-3 (ajulemic acid) is a synthetic analogue of a metabolite of Delta9-tetrahydrocannabinol that has reported analgesic efficacy in neuropathic pain states in man. Here we show that CT-3 binds to human cannabinoid receptors in vitro, with high affinity at hCB1 (Ki 6 nM) and hCB2 (Ki 56 nM) receptors. In a functional GTP-gamma-S assay CT-3 was an agonist at both hCB1 and hCB2 receptors (EC50 11 and 13.4 nM, respectively). In behavioural models of chronic neuropathic and inflammatory pain in the rat, oral administration of CT-3 (0.1-1 mg/kg) produced up to 60% reversal of mechanical hyperalgesia. In both models the antihyperalgesic activity was prevented by the CB1-antagonist SR141716A but not the CB2-antagonist SR144528. In the tetrad of tests for CNS activity, CT-3 (1-10 mg/kg, po) produced dose-related catalepsy, deficits in locomotor performance, hypothermia, and acute analgesia. Comparison of 50% maximal effects in the tetrad and chronic pain assays produced an approximate therapeutic index of 5-10. Pharmacokinetic analysis showed that CT-3 exhibits significant but limited brain penetration, with a brain/plasma ratio of 0.4 measured following oral administration, compared to ratios of 1.0-1.9 measured following subcutaneous administration of WIN55,212-2 or Delta9-THC. These data show that CT-3 is a cannabinoid receptor agonist and is efficacious in animal models of chronic pain by activation of the CB1 receptor. Whilst it shows significant cannabinoid-like CNS activity, it exhibits a superior therapeutic index compared to other cannabinoid compounds, which may reflect a relatively reduced CNS penetration. Topics: Analgesics; Animals; Benzoxazines; Cannabinoids; Catalepsy; Cell Line; Chromatography; Cricetinae; Cricetulus; Cyclohexanols; Disease Models, Animal; Dose-Response Relationship, Drug; Dronabinol; Drug Interactions; Freund's Adjuvant; Guanosine 5'-O-(3-Thiotriphosphate); Humans; Hypothermia; Inflammation; Ligation; Male; Morpholines; Motor Activity; Naphthalenes; Pain; Pain Measurement; Pain Threshold; Radioligand Assay; Rats; Rats, Wistar; Rotarod Performance Test; Sciatic Neuropathy; Sulfur Isotopes; Time Factors; Tritium | 2005 |
Behavioral pharmacological properties of a novel cannabinoid 1',1'-dithiolane delta8-THC analog, AMG-3.
Newly developed cannabinoids may hold the promise of the development of useful and safe drugs. This study aimed to investigate the behavioral effects of the novel 1',1'-dithiolane delta8-HC analogue AMG-3, a cannabinomimetic molecule with high affinity for CB1/CB2 receptors. This analog was chosen for its binding affinity to these receptors, which is higher than that reported for delta8-tetrahydrocannabinol (delta8-THC). Behavioral responses were assessed after the administration of AMG-3 (1, 2, 4, 8 mg/kg, i.p.) in the open field, on the bar test, on the hot plate and in the intracranial self-stimulation procedure. AMG-3 increased the reactivity time on the hot plate in a dose- and time-dependent manner, indicating a long-lasting analgesic effect (at least 24 h). The substance was found dose-dependently to decrease spontaneous motor activity and to induce catalepsy, particularly at the highest dose (8 mg/kg). AMG-3 did not affect the rewarding value of intracranial self-stimulation, except to increase the reward threshold at the highest dose (8 mg/kg). The effects of the highest dose of AMG-3 on spontaneous activity and on the self-stimulation paradigm were completely reversed by pre-treatment with the CB1 receptor antagonist AM-251. These findings indicate that the administration of AMG-3 to rats elicits a specific behavioral profile, most probably associated with the activation of CB1 receptors and without effects indicating abuse potential. Topics: Animals; Behavior, Animal; Binding, Competitive; Cannabinoids; Catalepsy; Cell Membrane; Cerebral Cortex; Cyclohexanols; Dose-Response Relationship, Drug; Male; Molecular Structure; Motor Activity; Pain; Pain Measurement; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Time Factors; Tritium | 2005 |
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. Topics: Analgesics; Analysis of Variance; Animals; Behavior, Animal; Camphanes; Cyclohexanols; Dose-Response Relationship, Drug; Drug Administration Routes; Drug Interactions; Ligation; Male; Nociceptors; Pain; Pain Measurement; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Reaction Time; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Rimonabant; Spinal Nerves; Time Factors | 2004 |
'Knock-down' of spinal CB1 receptors produces abnormal pain and elevates spinal dynorphin content in mice.
Recent studies demonstrate the possible existence of tonic modulatory control of nociceptive input mediated by spinal cannabinoid receptors (CB1). Accordingly, it is predicted that a reduction in the spinal CB1 receptors may enhance sensitivity to sensory stimuli and a decrease in spinal antinociceptive potency to cannabinoid agonists. An antisense oligodeoxynucleotide (ODN) specific to the CB1 receptor was used to 'knock-down' CB1 receptors in the lumbar spinal cord and dorsal root ganglia by the local, repeated intrathecal (i.th.) administration of the ODN. This treatment resulted in a decrease in lumbar spinal CB1 receptor expression accompanied by a decrease in the response thresholds to both innocuous tactile and noxious thermal stimuli. The antinociceptive action of the CB1 agonist, WIN 55,212-2, by i.th. administration was also significantly attenuated after treatment with the antisense ODN. Similar treatment using a mismatch control ODN had no effect on receptor protein or on sensory thresholds. The effects of the antisense ODN treatment on sensory thresholds were fully reversed after discontinuation of the ODN injection. The antisense ODN treated rats also showed a significant increase in lumbar spinal dynorphin A. Acute i.th. injection of MK-801 or an antidynorphin antiserum blocked the antisense ODN-induced tactile and thermal hypersensitivity. These data support the possibility of endogenous inhibitory cannabinoid tone to limit spinal afferent input of thermal and tactile stimuli. Lifting of this inhibitory tone through a 'knock-down' of spinal CB1 receptors apparently lowers the thresholds for sensory input, as reflected by the actions of MK-801 to block tactile and thermal hypersensitivity. The increased spinal dynorphin may act to further promote afferent outflow and abnormal pain because sequestration of spinal dynorphin with antiserum also reverses the manifestations of abnormal pain following knock-down of CB1 receptors. Topics: Analgesics; Animals; Antibodies; Benzoxazines; Cyclohexanols; Dizocilpine Maleate; Dynorphins; Excitatory Amino Acid Antagonists; Male; Mice; Mice, Inbred ICR; Morpholines; Naphthalenes; Oligodeoxyribonucleotides, Antisense; Pain; Receptors, Cannabinoid; Receptors, Drug; Spinal Cord; Tritium | 2002 |
Dynorphin B and spinal analgesia: induction of antinociception by the cannabinoids CP55,940, Delta(9)-THC and anandamide.
The endogenous opioid dynorphin B was evaluated for its role in cannabinoid-induced antinociception. Previous work in our laboratory has shown that the synthetic, bicyclic cannabinoid, CP55,940, induces the release of dynorphin B whilst the naturally occurring cannabinoid, Delta(9)-tetrahydrocannabinol (Delta(9)-THC), releases dynorphin A. The dynorphins contribute in part to the antinociceptive effects of both cannabinoids at the level of the spinal cord. The present study compares dynorphin B released from perfused rat spinal cord in response to acute administration of anandamide (AEA), Delta(9)-THC and CP55,940 at two time points, 10 min and 30 min post administration, and attempts to correlate such release with antinociceptive effects of the drugs. Dynorphin B was collected from spinal perfusates of rats pretreated with Delta(9)-THC, CP55,940 or AEA. The supernatant was lyophilized and the concentrations of dynorphin B were measured via radioimmunoassay. At a peak time of antinociception (10 min), CP55,940 and Delta(9)-THC induced significant two-fold increases in the release of dynorphin B. AEA did not significantly release dynorphin B. Upon a 30-min pretreatment with the drugs, no significant dynorphin B release was observed, although antinociceptive effects persisted for CP55,940 and Delta(9)-THC. Previous work indicates that Delta(9)-THC releases dynorphin A while AEA releases no dynorphin A. This study confirms that although all three test drugs produced significant antinociception at 10 min, the endocannabinoid, AEA, does not induce antinociception via dynorphin release. Thus, our data indicate a distinct mechanism which underlies AEA-induced antinociception. Topics: Analgesia; Analgesics; Analgesics, Non-Narcotic; Animals; Arachidonic Acids; Calcium Channel Blockers; Cannabinoid Receptor Modulators; Cannabinoids; Cyclohexanols; Dronabinol; Dynorphins; Endocannabinoids; Endorphins; Male; Pain; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley; Spinal Cord | 2000 |
Cannabinoid modulation of dynorphin A: correlation to cannabinoid-induced antinociception.
Intrathecal administration of anandamide, delta9-tetrahydrocannabinol (THC) and (-)-3-[2-hydroxy-4-(1,1-dimethyheptyl)ptyl)phenyl]-4-(3-hydr oxypropyl)-cicloexan-1-ol (CP55,940) induced spinal antinociception accompanied by differential kappa-opioid receptor involvement and dynorphin A peptide release. Antinociception using the tail-flick test was induced by the classical cannabinoid THC and was blocked totally by 17,17'-bis(cyclopropylmethyl)-6',6,7,7'-tetrahydro-4,5,4'5'-diepoxy++ +-6,6'-(imino)[7,7'-bimorphinan]-3,3',14,14'-tetrol (norbinaltorphimine) indicating a significant and critical kappa-opioid receptor component. The endogenous cannabinoid, anandamide and the non-classical bicyclic cannabinoid, CP55,940, induced non-nor-BNI-sensitive effects. The N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazo le-carboxamide (SR141716A)-mediated attenuation of spinal antinociception imparted by the various cannabinoids indicates cannabinoid CB1 receptor involvement. THC-induced an enhancement of immunoreactive dynorphin A release which coincided with the onset, but not duration antinociception. The release of dynorphin A was also attenuated by SR141716A suggesting it is cannabinoid CB1 receptor-mediated. These data indicate a critical role for dynorphin A release in the initiation of the antinociceptive effects of the cannabinoids at the spinal level. Topics: Analgesics; Animals; Cannabinoids; Cyclohexanols; Dimethyl Sulfoxide; Dronabinol; Dynorphins; Injections, Spinal; Male; Naltrexone; Narcotic Antagonists; Nociceptors; Pain; Pain Measurement; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Rimonabant | 1999 |
Intrathecal cannabinoid administration suppresses noxious stimulus-evoked Fos protein-like immunoreactivity in rat spinal cord: comparison with morphine.
To determine whether cannabinoids suppress noxious stimulus-evoked Fos protein-like immunoreactivity (FLI) through direct actions at the spinal level.. Rats were implanted with intrathecal (ith) catheters at least one week prior to evaluation in the formalin test. Effects of the cannabinoid agonist, CP55,940 (80 micrograms ith) on formalin pain and FLI in rat spinal cord were compared with that of the prototypic narcotic analgesic, morphine (20 micrograms ith). CP55,940 suppressed pain behavior and FLI induced by intraplantar formalin. The cannabinoid suppressed Fos in the neck region of the dorsal horn and in the ventral horn, but not in the nucleus proprius. The efficacy of the cannabinoid in suppressing FLI in these laminae and pain behavior was comparable to morphine administered via the same route. However, only morphine suppressed FLI in the superficial dorsal horn relative to vehicle treatment.. Cannabinoids suppress nociceptive processing, in part, through actions at the spinal level. However, morphine showed greater potency and efficacy than CP55,940 in suppressing formalin-induced FLI following spinal administration. Topics: Analgesics; Animals; Cannabinoids; Cyclohexanols; Immunosuppressive Agents; Injections, Spinal; Male; Morphine; Nociceptors; Pain; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Spinal Cord | 1999 |
Evaluation of agonist-antagonist properties of nitrogen mustard and cyano derivatives of delta 8-tetrahydrocannabinol.
delta 8-Tetrahydrocannabinol (delta 8-THC) is a naturally occurring cannabinoid with a characteristic pharmacological profile of in vivo effects. Previous studies have shown that modification of the structure of delta 8-THC by inclusion of a nitrogen-containing functional group alters this profile and may alkylate the cannabinoid receptor, similar to the manner in which beta-funaltrexamine (beta-FNA) alkylates the micro-opioid receptor. Two novel analogs of delta 8-THC were synthesized: a nitrogen mustard analog with a dimethylheptyl side chain (NM-delta 8-THC) and a cyano analog with a dimethylpentyl side chain (CY-delta 8-THC). Both analogs showed high affinity for brain cannabinoid receptors and when administered acutely, produced characteristic delta 9-THC-like effects in mice, including locomotor suppression, hypothermia, antinociception and catalepsy. CY-delta 8-THC shared discriminative stimulus effects with CP 55,940; for NM-delta 8-THC, these effects also occurred, but were delayed. Although both compounds attenuated the effects of delta 9-THC in the mouse behavioral tests, evaluation of potential antagonist effects of these compounds was complicated by the fact that two injections of delta 9-THC produced similar results, suggesting that acute tolerance or desensitization might account for the observations. NM-delta 8-THC, but not CY-delta 8-THC, attenuated the discriminative stimulus effects of CP 55,940 in rats several days following injection. Hence, addition of a nitrogen-containing functional group to a traditional cannabinoid structure does not eliminate agonist effects and may produce delayed attenuation of cannabinoid-induced pharmacological effects. Topics: Animals; Body Temperature Regulation; Cannabinoids; Catalepsy; Cyclohexanols; Dronabinol; Male; Maze Learning; Mice; Mice, Inbred ICR; Motor Activity; Nitrogen Mustard Compounds; Pain; Rats; Rats, Sprague-Dawley; Receptors, Cannabinoid; Receptors, Drug; Structure-Activity Relationship | 1996 |