Cannabinoid Mechanisms of Pain Suppression 5293.4.2
Role of Rostral Ventral Medulla
Researchers have targeted synthetic cannabinoids at other brainstem nuclei in-
cluding the RVM (Martin et al. 1998; Monhemius et al. 2001; Vaughan et al. 1999)
and the nucleus reticularis gigantocellularis (Monhemius et al. 2001) to better
characterize sites of cannabinoid-mediated antinociception. Site-specific admin-
istration of cannabinoids (WIN55,212-2 and HU210) in the RVM produced signif-
icant antinociception in the tail-flick test (Martin et al. 1998). Mediation by CBRs
was established because the antinociceptive effects of HU210 were blocked by the
CB1R antagonist SR141716A, and the receptor-inactive enantiomer WIN55,212-3
failed to induce antinociception following microinjection to the same site (Martin
et al. 1998).
Electrophysiological studies have provided insight into the mechanisms medi-
ating these antinociceptive effects. Cannabinoids modulate on- and off-cells in the
RVM (Meng et al. 1998), demonstrating their ability to control descending pain
modulatory signaling in a manner similar to that of morphine. Pharmacological
inactivation of the RVM with site-specific administration of the GABAAreceptor
agonist muscimol blocked the antinociceptive effects but not the motor deficits of
systemically administered WIN55,212-2 (Meng et al. 1998). At the cellular level, it
appears that cannabinoids exert their physiological effects in the RVM by presy-
naptic inhibition of GABAergic neurotransmission (Vaughan et al. 1999).
3.4.3
Role of the Basolateral Amygdala
The amygdala is a nuclear complex located in the limbic forebrain that plays a key
role in the coordination of fear and defensive reactions. The amygdala is optimally
positioned anatomically to receive and integrate sensory information from multi-
ple modalities and, in turn, to mediate emotional, autonomic, and somatic motor
reactions to salient stimuli (especially threatening stimuli) (Davis and Whalen
2001). Within the amygdala, CB1R immunoreactivity has been detected in a subset
of GABAergic interneurons in the basolateral complex (Marsicano et al. 2002),
a site implicated in the formation and storage of aversive memories (Medina et
al. 2002). Endocannabinoids are elevated in the basolateral amygdala in a condi-
tioned fear-aversion paradigm (Marsicano et al. 2002), supporting the hypothesis
that endocannabinoids serve naturally to inhibit extinction of aversive memories.
Presentation of the conditioned aversive stimulus during extinction trials elicited
elevated levels of the endocannabinoids 2-arachidonoylglycerol (2-AG) and anan-
damide in the basolateral nucleus of the amygdala but not the medial prefrontal
cortex (another brain area implicated in memory formation) of mice. Marsicano
et al. (2002) reported that endocannabinoids and CB1Rs in the basolateral nucleus
of the amygdala are crucial to the long-term depression of GABAergic inhibitory
currents, positing that endocannabinoids regulate aversive memory extinction via
selective inhibition of local inhibitory networks in the amygdala.