Endocannabinoids and pain: spinal and peripheral analgesia in inflammation and neuropathy.

Analgesia is an important physiological function of the endocannabinoid system and one of significant clinical relevance. This review discusses the analgesic effects of endocannabinoids at spinal and peripheral levels, firstly by describing the physiological framework for analgesia and secondly by reviewing the evidence for analgesic effects of endocannabinoids obtained using animal models of clinical pain conditions. In the spinal cord, CB(1) receptors have been demonstrated in laminae of the dorsal horn intimately concerned with the processing of nociceptive information and the modulation thereof. Similarly, CB(1) receptors have been demonstrated on the cell bodies of primary afferent neurones; however, the exact phenotype of cells which express this receptor requires further elucidation. Local administration, peptide release and electrophysiological studies support the concept of spinally mediated endocannabinoid-induced analgesia. Whilst a proportion of the peripheral analgesic effect of endocannabinoids can be attributed to a neuronal mechanism acting through CB(1) receptors expressed by primary afferent neurones, the antiinflammatory actions of endocannabinoids, mediated through CB(2) receptors, also appears to contribute to local analgesic effects. Possible mechanisms of this CB(2)-mediated effect include the attenuation of NGF-induced mast cell degranulation and of neutrophil accumulation, both of which are processes known to contribute to the generation of inflammatory hyperalgesia. The analgesic effects of cannabinoids have been demonstrated in models of somatic and visceral inflammatory pain and of neuropathic pain, the latter being an important area of therapeutic need. Analgesia is one of the principal therapeutic targets of cannabinoids. This review will discuss the analgesic effects of endocannabinoids in relation to two areas of therapeutic need, persistent inflammation and neuropathic pain. The more general aspects of the role of cannabinoids, endogenous and exogenous, in analgesia have been recently reviewed elsewhere (Rice, Curr Opi Invest Drugs 2001; 2: 399-414; Pertwee, Prog Neurobil 2001; 63: 569-611; Rice, Mackie, In: Evers A. S, ed. Anesthetic Pharmacology: Physiologic Principles and Clinical Practice. St. Louis: Harcourt Health Sciences, 2002). Since a major goal in the development of cannabinoid-based analgesics is to divorce the antinociceptive effects from the psychotrophic effects, the discussion will focus on the antinociceptive effects produced at the spinal cord and/or peripheral level as these areas are the most attractive targets in this regard. A mechanistic discussion of the "framework" for analgesia will be followed by a description of studies examining the role of endocannabinoids in relieving pain; since the elucidation of these effects was undertaken using synthetic cannabinoids, reference will also be made to such studies, in the context of endocannabinoids.