Review
Cannabinoids: a real prospect for pain relief

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Abstract

Research on the therapeutic potential of cannabinoids has grown dramatically over the past few years. Recent advances include evidence that cannabinoid agonists are antihyperalgesic and antiallodynic in models of neuropathic pain. Development of novel cannabinoid agonists and cannabinoid preparations that are antinociceptive has important implications for the therapeutic use of this class of drugs.

Introduction

Painful stimuli are detected and encoded by primary afferent nociceptors, which relay noxious information to the spinal cord and the brain. The main ascending pain pathways are the spinothalamic and spinoparabrachial pathways, which subserve spatial discriminatory and emotional aspects of pain processing, respectively. The pharmacological management of pain, in particular chronic pain, can target peripheral nerves, spinal cord or the brain. Indeed, the mainstay analgesic morphine produces analgesia by acting at many different levels of the nociceptive pathway.

Endogenous cannabinoid mechanisms also exist at various levels in the pain pathway, in a system that is distinct from, but parallel to, that involving opiates. Cannabis was widely used in the 19th century for pain relief and there is renewed interest in cannabis-based medicines, with pain as one of the key therapeutic targets [1].

The discovery of the endogenous cannabinoid system, the availability of potent cannabinoid receptor antagonist drugs and receptor knockout mice has facilitated recent research progress on this topic. This review summarises current understanding of the involvement of the cannabinoid system in pain sensation and discusses the evidence that cannabinoid receptor ligands could be useful therapeutic agents for pain control.

Section snippets

Cannabinoid receptor localisation

Two types of cannabinoid receptors have been identified; cannabinoid CB1 receptors are located mostly in the central nervous system but are also expressed by peripheral neurones, and CB2 receptors are predominantly confined to the periphery. Both are seven-transmembrane receptors coupled to Gi/o proteins.

Cannabinoid CB1 receptors are located at many of the sites associated with peripheral and central processing of nociceptive messages. In situ hybridisation studies suggest that medium and

Pharmacological evidence from animal studies that cannabinoids are antinociceptive

Systemically administered cannabinoid agonists have demonstrable antinociceptive and antihyperalgesic effects in behavioural 6•., 7••., 8., 9., 10., 11. and electrophysiological 12., 13., 14. studies of acute and inflammatory nociception. The sites of action of cannabinoids have been extensively studied; antinociceptive effects of cannabinoids have been widely reported following peripheral, spinal and intracerebroventricular (i.c.v.) administration of different classes of cannabinoid receptor

Evidence from studies with knockout animals

Mice with a disrubted CB1 receptor gene have been generated; these CB1 receptor knockout mice have an increased mortality rate, reduced locomotor activity, increased catalepsy and hypoalgesia [40]. Results obtained with CB1 receptor knockout mice suggest that this receptor does not account for all the biological actions of anandamide. In particular, although the antinociceptive actions of Δ9-THC are virtually absent in such animals, anandamide continued to show analgesic activity in the

Interactions between endogenous cannabinoids and the vanilloid receptor

Given the evidence from knockout studies, there appear to be alternative receptors at which anandamide can act. A prime candidate is the vanilloid VR1 receptor [45••], which mediates pain responses to noxious heat or changes in pH and can be activated by exogenous application of capsaicin, the hot component of chilli peppers. Although anandamide has an affinity for the VR1 receptor in vitro that is 5-fold to 20-fold lower than its affinity for the CB1 receptor, Di Marzo et al. [45••] argue that

Conclusions and future directions

Basic research into the role of cannabinoids in pain mechanisms is progressing rapidly. The emerging concept is that the cannabinoid signalling system functions as a parallel but distinct mechanism from the opioids in modulating pain responses [53••]. Clinical progress, however, has been much slower. In the UK, the Medical Research Council has sponsored a large-scale controlled clinical trial of cannabis extract (oral) versus Δ9-THC or placebo (oral) in postoperative pain (House of Lords Report

Update

Recent work has demonstrated peripheral CB2 receptor mediated antinociception in the rat [60]. Peripheral injection of AM121, a CB2 receptor agonist, produced antinociception to thermal stimuli but did not produce the central cannabinoid effects of hypothermia, catalepsy or inhibition of locomotor activity. The authors suggest that CB2 receptor agonists may be clinically effective analgesics in the absence of central cannabinoid side effects.

Acknowledgements

The authors thank Steve Alexander and Dave Kendall for their helpful discussion.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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