Activation of cannabinoid CB2 receptors suppresses chemotherapy-induced neuropathy in rats
Rahn, Elizabeth Jocelyn
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The cannabinoid system is a recently discovered neurotransmitter system that shares the same pharmacological target as the primary active constituent in cannabis, 9-tetrahydrocannabinol. The cannabinoid system consists of two primary endogenous neurotransmitters (anandamide and 2-arachidonoylglycerol) as well as at least two metabotropic receptors (CB1 and CB2). Activation of the CB1 receptor is associated with psychotropic and motor effects, whereas activation of the CB2 receptor lacks these central nervous system side effects. The cannabinoid receptors have disparate distributions in the body, which may account for their differential side effect profiles. The CB1 receptor is localized primarily within the central nervous system (CNS). The CB2 receptor was originally believed to be restricted to immune cells in the periphery; however recent suggests indicates the presence of this receptor at low levels within the CNS. The present studies focus on the cannabinoid CB2 receptor as a potential target for novel analgesics. Antinociceptive properties of the purported cannabinoid CB2 receptor agonists, (R,S)-AM1241, (R)-AM1241, (S)-AM1241, AM1714, and AM1710 were assessed in response to both mechanical and thermal stimulation to better characterize these drugs. All four drugs produced robust antinociception in response to thermal, but not mechanical stimulation. The antinociceptive profile of AM1714 and at high doses, AM1710, involved activation of the cannabinoid CB1 receptor, whereas effects of (R,S)-AM1241 and its enantiomers were mediated exclusively by the cannabinoid CB2 receptor. (R,S)-AM1241, AM1714, and AM1710 failed to show CNS side effects at doses that produced robust antinociception to thermal stimulation. The final series of experiments assessed the efficacy of cannabinoid CB2-preferring agonists in a model of chemotherapy-induced neuropathy. (R,S)-AM1241, (R)-AM1241, and AM1714 attenuated established mechanical allodynia observed in animals treated with the chemotherapeutic agent paclitaxel. Prophylactic administration of the CB2-preferring agonist, AM1710, the mixed cannabinoid CB1/CB2 agonist, WIN55,212-2, and the neuropathic pain medication, gabapentin, suppressed the development of paclitaxel-induced neuropathic nociception with equal efficacy. All three drugs produced a protective effect against the development of neuropathy that was present up to two weeks following removal of the drug. Collectively, the data presented herein suggests that the cannabinoid CB2 receptor is a viable pharmacological target with immense potential for analgesic development with limited adverse side effects.