J. Manzanares1, J.J. Fernández-Ruiz2, J.A. Fuentes3, A.J. Carrascosa4 and J.A. Ramos2
1Servicio de Psiquiatría and 4Servicio de Anestesiología, Hospital Universitario 12 de Octubre, 28041, Madrid, Spain. 2Departamento de Bioquímica y Biología Molecular III and 3Departamento de Farmacología and Instituto Pluridisciplinar, Universidad Complutense, 28040-Madrid
In recent years, an endogenous cannabinoid signalling system has been described to play a regulatory role within the brain and also in the periphery. This regulatory system is composed of (i) at least two specific cannabinoid (CB1 –present in the CNS, peripheral neurons and also in certain non-neural tissues-, and CB2 –present preferentially in the immune system-receptor subtypes, both seven-transmembrane domain receptors coupled to GTP-binding proteins, (ii) a variety of endogenous cannabinoid ligands (anandamide, 2-arachidonoylglycerol) that are derivatives of arachidonic acid, and (iii) a process of termination of the biological action of endocannabinoids that involves a carrier-mediated uptake system and a degradative enzyme, called fatty acid amidohydrolase (Pertwee, 2001). Within the brain, this endocannabinoid system seems to play a modulatory role in several processes such as, pain, control of movement, regulation of body temperature, emesis, appetite, learning and memory, cognition and neuroendocrine control.
The control of nociception is a relevant function of the endocannabinoid system and one of the most promising effects from a therapeutic point of view (Fuentes et al., 1999; Robson, 2001; Campbell et al., 2001). Cannabinoid antinociceptive activity is produced at central and peripheral levels. At the central level, various brain regions have been involved, mainly, the midbrain, brainstem, periaqueductal grey matter, thalamic structures and the spinal cord. In these regions, the distribution of CB1 receptors is closely related to the antinociceptive activity of cannabinoids, however, the density of CB1 receptors in the spinal cord is lower than in brain areas. On the other hand, although CB2 receptors are predominantly located in the immune system in relation to their function of cannabinoid as immunomodulator agents, it has also been proposed that the activation of CB2 receptors may regulate pain initiation at sites of tissue injury. In rats, it has been suggested that both CB1 and CB2 receptors may be synthesized in dorsal root ganglia (entrance of the nociceptive stimulus in the spinal cord) and functional evidence indicates that CB1 receptors are axonally transported to peripheral fine endings of primary afferent nerve fibres (for review see Iversen and Chapman, 2002).
Central antinociceptive action exerted by cannabinoids occur at both supraspinal and spinal levels (Fox et al., 2001). The existence of a supraspinal level is confirmed by data showing that the antinociceptive effects of a intracerebroventricular administration of cannabinoids and by indirect evidence showing that systemic administration of cannabinoids was attenuated, but not completely blocked, by spinal transection. In addition, the relevance of supraspinal cannabinoid modulation of pain processing has gained impact by the fact that peripheral noxious stimulation results in the release of anandamide in the periaqueductal grey matter. Spinal action has been confirmed by intradural administration of cannabinoids.
On the other hand, it is interesting to note that acute administration of cannabinoid agonists results in an increase in the release of endogenous opioid ligands such as enkephalins and dynorphins, a fact that has been confirmed by the increase in opioid gene expression in the brain and spinal cord after subchronic (5 days) treatment with cannabinoid agonists (Manzanares et al., 1999). This action may support, at least in part, the synergistic antinociceptive activity induced by subeffective doses of opiate and cannabinoid agonists.
The antinociceptive activity of cannabinoids has been demonstrated in acute and chronic pain animal models by using different routes of administration (oral, subcutaneous, intramuscular, intravenous, intradural, intracerebroventricular) of these compounds. This action is dose-dependent and exhibits a potency similar to morphine. In contrast, clinical studies conclude that antinociception is dose- dependent presenting a potency similar to codeine. Side-effects are also dose-related and consisted of slurred speech, sedation, mental clouding, blurred vision, dizziness and ataxia (for review see Ashton, 1999). Cardiovascular side effects (hypotension, alterations in heart rate) are moderate and well tolerated. The main problem for chronic administration is probably the development of tolerance and dependence.
In conclusion, the hypoalgesic action of cannabinoids is well documented and considered timely and clinically promising, although the delay in the elucidation of molecular sites of action for cannabinoids compared with that for opioids has hampered a rapid clarification of pain-depressing effects of cannabinoids and, hence, their potential uses as analgesics.
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