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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