Hypoactivity of the Spinal Cannabinoid System Results in NMDA-Dependent Hyperalgesia

Abstract

Cannabinoids, such as Delta9-THC, are capable of inhibiting nociception, i.e., pain transmission, at least in part, by interacting with spinal Gi/Go-coupled cannabinoid receptors. What is not known, however, is the antinociceptive role of endogenous spinal cannabinoids. If endogenous cannabinoids modulate basal nociceptive thresholds, then alterations in this system could be involved in the etiology of certain pain states. In this report we provide evidence for tonic modulation of basal thermal nociceptive thresholds by the spinal cannabinoid system. Administration of oligonucleotides directed against CB1 cannabinoid receptor mRNA significantly reduced spinal cannabinoid binding sites and produced significant hyperalgesia when compared with a randomer oligonucleotide control. A second method used to reduce activity of the spinal cannabinoid receptor was intrathecal administration of the cannabinoid receptor antagonist SR 141716A. SR 141716A evoked thermal hyperalgesia with an ED50 of 0.0012 fmol. The SR 141716A-induced hyperalgesia was dose-dependently blocked by the administration of D-AP-5 or MK-801, two antagonists to the NMDA receptor. These results indicate that there is tonic activation of the spinal cannabinoid system under normal conditions. Furthermore, hypoactivity of the spinal cannabinoid system results in an NMDA-dependent hyperalgesia and thus may participate in the etiology of certain chronic pain states.

Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CB1 receptor knockout mice

“…Moreover, blockade of the CB1 receptor with the antagonist SR141716A produces hyperalgesia (37,38) and stimulates locomotor activity (39). The differences between the pharmacological results and this genetic study may be accounted for by the inverse agonist properties of SR141716A (40), or by differences in acute vs. chronic inactivation of the CB1 receptor.…”

Cannabinoids reduce hyperalgesia and inflammation via interaction with peripheral CB1 receptors

“…Although binding studies have found peripheral tissues to be negative for cannabinoid binding sites (Jansen et al, 1992;Lynn and Herkenham, 1994;RinaldiCarmona et al, 1996), CB 1 cannabinoid receptor mRNA is detectable in a number of peripheral tissues (Galiègue et al, 1995;. We have previously demonstrated that activation of spinal CB 1 receptors can result in both antihyperalgesia and inhibition of neuropeptide release from central terminals of capsaicin-sensitive primary afferent nociceptive fibers (Richardson et al, 1998b). Additionally, we have demonstrated that cannabinoid binding sites can be measured in sensory neurons (Richardson et al, 1998b).…”

“…We have previously demonstrated that activation of spinal CB 1 receptors can result in both antihyperalgesia and inhibition of neuropeptide release from central terminals of capsaicin-sensitive primary afferent nociceptive fibers (Richardson et al, 1998b). Additionally, we have demonstrated that cannabinoid binding sites can be measured in sensory neurons (Richardson et al, 1998b). Hohmann and Herkenham (1997) have reported that CB 1 receptor mRNA is expressed in substance P containing neurons in the dorsal root ganglia.…”

The endocannabinoid system as a target for therapeutic drugs

“…CB 1 receptors are also expressed in the dorsal root ganglia by a subset of small-and large-diameter sensory neurons that contain the pain-stimulating peptides, substance P and ␣-calcitonin gene-related peptide (CGRP) 32 . Although quantitatively small, the presence of CB 1 receptors on CGRPcontaining neurons appears to be functionally significant because CB 1 receptor agonists effectively reduce CGRP release from dorsal horn tissue 33 . Immunohistochemical experiments suggest that CB 1 receptors are present not only on central terminals of primary sensory afferents, but also on their peripheral counterparts 34 (Fig.…”