Cannabinoids and pain.

Convincing evidence from preclinical studies demonstrates that cannabinoids can reduce pain responses in a range of inflammatory and neuropathic pain models. The anatomical and functional data reveal cannabinoid receptor-mediated analgesic actions operating at sites concerned with the transmission and processing of nociceptive signals in brain, spinal cord and the periphery. The precise signalling mechanisms by which cannabinoids produce analgesic effects at these sites remain unclear; however, significant clues point to cannabinoid modulation of the functions of neurone and immune cells that mediate nociceptive and inflammatory responses. Intracellular signalling mechanisms engaged by cannabinoid receptors-like the inhibition of calcium transients and adenylate cyclase, and pre-synaptic modulation of transmitter release-have been demonstrated in some of these cell types and are predicted to play a role in the analgesic effects of cannabinoids. In contrast, the clinical effectiveness of cannabinoids as analgesics is less clear. Progress in this area requires the development of cannabinoids with a more favourable therapeutic index than those currently available for human use, and the testing of their efficacy and side-effects in high-quality clinical trials.