Cannabinoid Mechanisms of Pain Suppression 523Peripheral CB1R Modulation of Nerve Injury-Induced Nociception
A role for CB1Rs in suppressing hyperalgesia and allodynia induced by nerve in-
juryhasbeendemonstratedinmultiplemodelsofneuropathicpain(Bridgeset
al. 2001; Fox et al. 2001; Herzberg et al. 1997; Mao et al. 2000). Fox and colleagues
demonstrated that intraplantar administration of WIN55,212-2 suppresses me-
chanical hyperalgesia following partial ligation of the sciatic nerve; these effects
were blocked by the CB1R antagonist/inverse agonist SR141716A administered
systemically (Fox et al. 2001). These data suggest a peripheral CB1R action in neu-
ropathic pain, although CB2R mechanisms were not assessed. WIN55,212-2 also
suppresses thermal hyperalgesia as well as mechanical and cold allodynia follow-
ing spinal nerve ligation (Bridges et al. 2001). These latter effects were blocked
by systemic administration of a CB1R but not a CB2R antagonist (Bridges et al.
2001), suggesting that the antihyperalgesic effects of systemically administered
WIN55,212-2 were mediated by CB1R (Bridges et al. 2001; Herzberg et al. 1997).
3.3
Antinociception Mediated by CB1R in Spinal Cord
3.3.1
Distribution of CBRs on Central Terminals of Primary Afferents
Receptors are typically bidirectionally transported from the soma to central and
peripheral terminals (Young et al. 1980). To identify afferents likely to contain
CBRs, Hohmann and Herkenham assessed their pre- and postsynaptic distribu-
tions in the spinal cord using receptor binding and quantitative autoradiography
(Hohmann et al. 1999a; Hohmann and Herkenham 1998). Destruction of sensory
C fibers with neonatal capsaicin treatment produced only modest (16%) decreases
in cannabinoid binding sites in the superficial dorsal horn, as measured by recep-
tor binding and quantitative autoradiography (Hohmann and Herkenham 1998).
These data suggest that a majority of spinal CBRs is not localized to central termi-
nals of primary afferent C fibers. Multisegment unilateral cervical dorsal rhizotomy
(C3-T1 or T2) produced time-dependent losses in cannabinoid binding densities
in the dorsal horn (Hohmann et al. 1999a) of larger magnitude than that induced
by neonatal capsaicin treatment. This observation is unsurprising because rhi-
zotomy destroys the central terminals of both small- and large-diameter fibers.
Rhizotomy suppressed [^3 H]CP55,940 binding in the superficial and neck region
of the dorsal horn as well as in the nucleus proprius without affecting binding in
lamina X or the ventral horn. By contrast, massive losses inμ-opioid binding sites
were observed in lamina I and II in adjacent sections following either neonatal
capsaicin or rhizotomy (Hohmann et al. 1999a; Hohmann and Herkenham 1998),
consistent with previous reports (Besse et al. 1990; Nagy et al. 1980). These data
support the conclusion that CB1Rs occur both pre- and postsynaptically in the
spinal dorsal horn, with the majority of receptors occurring postsynaptically. This
conclusion is consistent with the observation of CB1R-immunoreactive fibers in
dorsal roots (Sanudo-Pena et al. 1999) and in axons of Lissauer’s tract (Salio et