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Blunting Pain at a Distance

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Science Translational Medicine  20 Oct 2010:
Vol. 2, Issue 54, pp. 54ec162
DOI: 10.1126/scitranslmed.3001790

Sharp, sudden pain and dull, aching long-lasting pain: Both arise from myriad underlying conditions and lead to considerable worldwide disability. Although a number of neurotransmitter systems in both the central nervous system and the periphery are known to process pain signals, the relatively recent discovery that endocannabinoids also participate offers a fresh avenue for potential intervention. Naturally occurring cannabinoids such as Δ(9)-tetrahydrocannabinol, the main psychoactive ingredient in marijuana, are well known to modify pain perception through both central and peripheral cannabinoid receptors. The possibility that blockade of cannabinoid receptors located outside the brain and spinal cord could be exploited to attenuate pain raises an exciting prospect: pain relief for patients without centrally mediated side effects and risks such as effects on mood and cognition, tolerance, and risk of abuse.

The recent paper by Clapper and colleagues provides new information about the mechanism of peripheral control of pain by endocannabinoids that propels the field toward that goal. They used a newly described compound (URB937) that inhibits fatty acid amide hydrolase (FAAH), the enzyme that degrades the endocannabinoid anandamide. Administration of this compound, which does not penetrate the brain, to mice increased anandamide concentrations in peripheral tissue but not the brain and attenuated behavioral responses that are indicative of persistent pain from peripheral nerve injury and inflammation. URB937 also abolished spinal cord neural responses to noxious stimulation, suggesting that peripheral anandamide controls pain signals entry into the central nervous system. URB937’s effects were blocked by a CB1 receptor antagonist and in mice lacking FAAH, confirming the roles of these targets in mediating pain. Furthermore, URB937 did not affect the other major endocannabinoid, 2-arachidonoyl glycerol. These data from Clapper et al. suggest that anandamide, acting via peripheral CB1 receptors, is a key regulator of pain. They further offer intriguing evidence for a new target in the expanding pharmacological armamentarium against pain.

J. R. Clapper et al., Anandamide suppresses pain initiation through a peripheral endocannabinoid mechanism. Nat. Neurosci. 13, 1265–1270 (2010). [Abstract]

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