Cannabinoid Mechanisms of Pain Suppression 527effectsonA-βfiber-evoked responses (Kelly and Chapman 2001). Systemic and
intrathecally administered cannabinoids retain a weak but long-lasting antinoci-
ceptive effect in spinally transected rats (Lichtman and Martin 1991b; Smith and
Martin 1992), providing compelling evidence for spinal mechanisms of cannabi-
noid antinociception.
Spinal administration of a cannabinoid (HU210) also suppresses C fiber-
mediated post-discharge responses, a measure of neuronal hyperexcitability, in
carrageenan-inflamed and noninflamed rats (Drew et al. 2000); these effects were
blocked by a CB1R antagonist. Spinal administration of anandamide produced
CB1R-mediated effects in carrageenan-inflamed rats that were similar to that re-
ported for HU210, but only inconsistent effects were observed in noninflamed
rats (Harris et al. 2000). Upregulation of CB1Rs is also observed in the spinal
cord following nerve injury, suggesting that regulation of spinal CB1Rs may con-
tribute to the therapeutic efficacy of cannabinoids in neuropathic pain states (Lim
et al. 2003). These data implicate involvement of spinal CB1Rs in both acute and
persistent pain states.
3.4
Antinociception Mediated by CB1Rs in Supraspinal Pain Circuits
Support for supraspinal sites of cannabinoid antinociceptive action is derived
from the antinociceptive effects of cannabinoids following intracerebroventricu-
lar administration (Hohmann et al. 1999b; Martin et al. 1993) and the attenuation
of cannabinoid antinociception following disruption of communication between
brain and spinal cord. Both the antinociceptive (Lichtman and Martin 1991b)
and electrophysiological (Hohmann et al. 1999b) effects of systemically admin-
istered cannabinoids are attenuated following spinal transection, suggesting the
involvement of supraspinal sites of cannabinoid analgesic action. Intrathecal ad-
ministration of theα 2 antagonist yohimbine but not the serotonin antagonist
methysergide also blocks the antinociceptive effect of systemically administered
∆^9 -tetrahydrocannabinol (∆^9 -THC) (Lichtman and Martin 1991a). Furthermore,
the antinociceptive efficacy of systemically administered cannabinoids is markedly
attenuated following neurotoxic destruction of descending noradrenergic projec-
tions to the spinal cord (Gutierrez et al. 2003). These data collectively implicate
a role for descending noradrenergic systems in cannabinoid antinociceptive mech-
anisms.
Direct evidence for supraspinal sites of cannabinoid antinociception is derived
from studies employing intracranial administration of cannabinoids. Site-specific
injections of cannabinoid agonists to various brain regions have permitted the
identification of brain loci implicated in cannabinoid antinociception. The active
sites included the dorsolateral periaqueductal gray, dorsal raphe nucleus, RVM,
amygdala, lateral posterior and submedius regions of the thalamus, superior col-
liculus, and noradrenergic A5 region (Martin et al. 1995, 1998, 1999a). These stud-
ies suggest that endocannabinoid actions at these sites are sufficient to produce
antinociception.