Review
Spinal and peripheral mechanisms of cannabinoid antinociception: behavioral, neurophysiological and neuroanatomical perspectives

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Abstract

A large body of literature indicates that cannabinoids suppress behavioral responses to acute and persistent noxious stimulation. This review examines behavioral, neurophysiological and neuroanatomical evidence supporting a role for cannabinoids in suppressing nociceptive transmission at spinal and peripheral levels. The development of subtype-selective competitive antagonists and high-affinity agonists provides the pharmacological tools required to study cannabinoid antinociceptive mechanisms. These studies provide insight into the functional roles of cannabinoid receptor subtypes, CB1 and CB2, in cannabinoid antinociceptive mechanisms as revealed in animal models of acute and persistent (somatic inflammatory, visceral inflammatory, neuropathic) pain. Localization studies employing receptor binding and quantitative autoradiography, immunocytochemistry and in situ hybridization are reviewed to examine the distribution of cannabinoid receptors at these levels and provide a neuroanatomical framework with which to understand the roles of endogenous cannabinoids in sensory processing.

Section snippets

Functional significance of a cannabinoid transmitter system

The discovery of a G-protein-coupled cannabinoid receptor (Matsuda et al., 1990, Gerard et al., 1991) and identification of anandamide, the first isolated endogenous cannabinoid (Devane et al., 1992), established the existence of a cannabinoid transmitter system. The distribution of cannabinoid receptors in the central nervous system (Herkenham et al., 1991, Tsou et al., 1998) provides an anatomical basis for the profound effects of cannabinoids on behavior. Cannabinoid receptors are localized

Subtypes of cannabinoid receptors

Two cannabinoid receptor subtypes, CB1 and CB2, have been identified; CB1 is enriched in brain (Matsuda et al., 1990, Zimmer et al., 1999, Buckley et al., 2000) whereas CB2 is enriched in cells of the immune system (Munro et al., 1993, Lynn and Herkenham, 1994, Buckley et al., 2000). CB2 mRNA is found in cells associated with immune functions such as mast cells (Facci et al., 1995). The presence of CB1 (Hohmann et al., 1999a, Hohmann et al., 1999b, Ahluwalia et al., 2000, Ahluwalia et al., 2002

Cannabinoid receptor pharmacology

The development of competitive antagonists for CB1 (Rinaldi-Carmona et al., 1994) and CB2 (Rinaldi-Carmona et al., 1998) provide pharmacological tools for studying biological functions of cannabinoids. SR141716A binds to cannabinoid receptors in brain with high affinity (Kd=0.23 nM, Rinaldi-Carmona et al., 1994), but displays negligible affinity for CB2 (Ki(CB1 vs. CB2)=5.6 nM vs. >1 μM, Showalter et al., 1996). SR144528 (Rinaldi-Carmona et al., 1998) is a selective CB2 antagonist (Ki(CB1 vs.

Antinociceptive effects of cannabinoids

Cannabinoid antinociception is observed in behavioral studies employing different modalities of noxious stimulation including thermal, mechanical and chemical (see Walker et al., 2001 for review). The potency and efficacy of cannabinoid antinociception rivals that of morphine (Buxbaum, 1972, Bloom et al., 1977). However, cannabinoids also produce profound motor effects (e.g. immobility, catalepsy, Martin et al., 1991) that represent a confound for behavioral studies assessing motor responses to

Cannabinoid-induced suppression of nociceptive transmission

Electrophysiological and neurochemical studies provide convincing evidence that cannabinoids suppress nociceptive transmission in vivo (Hohmann et al., 1995, Hohmann et al., 1998, Hohmann et al., 1999b, Martin et al., 1996, Meng et al., 1998, Strangman and Walker, 1999, Tsou et al., 1996, Drew et al., 2000, Harris et al., 2000, Kelly and Chapman, 2001). Walker's laboratory first demonstrated that cannabinoids suppress noxious stimulus-evoked neuronal activity in nociceptive neurons in the

Acute pain

Antinociceptive effects of cannabinoids are mediated, in part, at the spinal level. Support for spinal mechanisms of cannabinoid analgesic action is derived from the ability of intrathecally administered cannabinoids to produce antinociception (Yaksh, 1981, Smith and Martin, 1992, Welch et al., 1995). The behavioral data are consistent with the ability of spinally administered cannabinoids to suppress noxious heat-evoked and afterdischarge firing in wide dynamic range neurons in rat lumbar

Localization of cannabinoid receptors in dorsal root ganglia and spinal cord

Cannabinoid receptors have been identified in rat spinal cord using autoradiographic (Herkenham et al., 1991, Hohmann and Herkenham, 1998, Hohmann et al., 1999a) and immunocytochemical (Tsou et al., 1998, Sañudo-Peña et al., 1999, Farquhar-Smith et al., 2000, Morisset et al., 2001, Salio et al., 2001, Salio et al., 2002b) techniques. It is important to note that localization studies employing antibodies raised against the N-terminal of the CB1 receptor protein reveal different patterns of

Summary

In the early 1990s, the neural mechanisms through which cannabinoids suppress pain were poorly understood, and it could not be stated with certainty that cannabinoids produced antinociception by suppressing nociceptive transmission rather than motor behavior. The discovery of cannabinoid receptors and endogenous cannabinoids set the stage for research demonstrating that: (1) cannabinoids suppress nociceptive processing, (2) this suppression involves supraspinal, spinal and peripheral

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