530 J.M. Walker and A.G. Hohmann
The amygdala also plays a critical role in modulating antinociception. Microin-
jection of cannabinoids into the basolateral nucleus of the amygdala produces
antinociception in the tail-flick test (Martin et al. 1999a). Microinjection ofμ-
opioid agonists into the basolateral nucleus of the amygdala similarly results in
marked antinociceptive responding in the radiant heat tail-flick (Helmstetter et
al. 1993, 1995) and formalin tests (Manning and Mayer 1995). Moreover, bilateral
lesions of the amygdala rendered nonhuman primates less sensitive to the antinoci-
ceptive effects of the potent synthetic cannabinoid WIN55,212-2 (Manning et al.
2001). In rodents, microinjection of the GABAAagonist muscimol into the central
nucleus of the amygdala but not into the basolateral nucleus of the amygdala, re-
duced the antinociceptive effects of systemic WIN55,212-2 (Manning et al. 2003).
Moreover, the endocannabinoid-degrading enzyme FAAH is localized in the ba-
solateral and lateral amygdala (Egertová et al. 2003; Tsou et al. 1998b). These data
indicate that a mechanism exists for inactivation of endocannabinoid actions in the
basolateral amygdala. Both conditioned (Helmstetter 1992; Helmstetter and Bell-
gowan 1993) and unconditioned (Bellgowan and Helmstetter 1996) stress-induced
analgesia depend on intact functioning of the amygdala. These observations, to-
gether with the demonstration of cannabinoid-mediated antinociceptive effects
following site-specific administration to the basolateral nucleus of the amygdala
(Martin et al. 1999a), suggest that endocannabinoids may serve naturally to sup-
press environmentally induced pain by actions in the amygdala.
4
Antinociception Mediated by CB2Rs
In clinical trials of THC and other cannabinoid agonists for pain pharmacotherapy,
unwanted, negative psychotropic effects limit dosing to levels that are probably
below those producing maximal analgesic efficacy. These effects are caused by
actions of the compounds at CB1Rs in the brain. However, CB2Rs are either absent
or expressed in low levels by neural tissues (Munro et al. 1993; Zimmer et al. 1999).
This distribution has led to evaluation and validation of CB2Rs as targets for novel
pharmacotherapies for pain.
4.1
Localization of CB2Rs that Contribute to Cannabinoid Antinociception
CB2Rs are expressed by cells that are involved in inflammation and thereby pain.
Among them are monocytes, polymorphonuclear neutrophils, mast cells, B cells,
T cells, and natural killer cells (see Cabral and Staab, this volume). CB2Rs are
also found on microglia (Walter et al. 2003), which play an important role in
pathological pain states (Zhang et al. 2003). Recent pharmacological evidence also
supports the presence of CB2Rs in human and guinea pig vagus nerve (Patel et
al. 2003). CB2R immunoreactivity has been detected in dorsal root ganglion cells
(Ross et al. 2001a) in cultures derived from neonatal rats. More work is necessary