Self-administration of a cannabinoid CB2 agonist in an animal model of neuropathic pain
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We evaluated the impact of neuropathic pain on the propensity of rats to self-administer the cannabinoid CB2 agonist AM1241. CB2 is prevalent outside the central nervous system (CNS) and is induced in the CNS by traumatic nerve injury. A unilateral spared nerve injury was performed to induce neuropathic pain. Control rats were subjected to a sham surgery and naive animals were intact. Animals were surgically implanted with an indwelling jugular catheter to allow intravenous drug self-administration. Mechanical withdrawal thresholds were evaluated in the left and right paws before and after surgical procedures and before and after each drug self-administration session. AM1241 self-administration, but not vehicle, increased mechanical withdrawal thresholds in the left (injured) paw in neuropathic rats. Changes in mechanical withdrawal thresholds were absent following AM1241 self-administration in naive and sham-operated groups. Self-administration, as defined by preferential responding on the active but not the inactive lever, was observed in neuropathic and sham-operated groups receiving AM1241 (day 1). No difference was observed in the number of active and inactive lever presses in rats self-administering vehicle. The CB2 antagonist SR144528 blocked the AM1241-induced suppression of nerve injury-induced tactile allodynia and attenuated active lever responding. The CB1 antagonist SR141716 induced hypersensitivity in the right (intact) paw in neuropathic and naive groups self-administering vehicle or AM1241. SR141716 induced hypersensitivity in paw withdrawal thresholds in the left (intact) paw in naive groups self-administering vehicle. SR141716 attenuated active and inactive lever presses in naive and neuropathic groups self-administering vehicle. Morphine self-administration elevated paw withdrawal thresholds in neuropathic rats, but not in naive or sham-operated groups. By day 2, naive and neuropathic groups self-administering morphine responded preferentially on the active and not the inactive lever. The maximally self-administered dose of AM1241 failed to induce motor deficits in naive or neuropathic groups in the rotarod test. Our data demonstrate that self-administration of AM1241 suppresses nerve injury-induced tactile allodynia. The observation that naive animals self-administered morphine but not AM1241 is consistent with the hypothesis that activation of CB2 is not inherently reinforcing and raises the possibility that CB2 agonists may represent a class of analgesics with low abuse liability.