Targeting CB2 receptors and the endocannabinoid system for the treatment of pain

Abstract

The endocannabinoid system consists of the cannabinoid (CB) receptors, CB(1) and CB(2), the endogenous ligands anandamide (AEA, arachidonoylethanolamide) and 2-arachidonoylglycerol (2-AG), and their synthetic and metabolic machinery. The use of cannabis has been described in classical and recent literature for the treatment of pain, but the potential for psychotropic effects as a result of the activation of central CB(1) receptors places a limitation upon its use. There are, however, a number of modern approaches being undertaken to circumvent this problem, and this review represents a concise summary of these approaches, with a particular emphasis upon CB(2) receptor agonists. Selective CB(2) agonists and peripherally restricted CB(1) or CB(1)/CB(2) dual agonists are being developed for the treatment of inflammatory and neuropathic pain, as they demonstrate efficacy in a range of pain models. CB(2) receptors were originally described as being restricted to cells of immune origin, but there is evidence for their expression in human primary sensory neurons, and increased levels of CB(2) receptors reported in human peripheral nerves have been seen after injury, particularly in painful neuromas. CB(2) receptor agonists produce antinociceptive effects in models of inflammatory and nociceptive pain, and in some cases these effects involve activation of the opioid system. In addition, CB receptor agonists enhance the effect of mu-opioid receptor agonists in a variety of models of analgesia, and combinations of cannabinoids and opioids may produce synergistic effects. Antinociceptive effects of compounds blocking the metabolism of anandamide have been reported, particularly in models of inflammatory pain. There is also evidence that such compounds increase the analgesic effect of non-steroidal anti-inflammatory drugs (NSAIDs), raising the possibility that a combination of suitable agents could, by reducing the NSAID dose needed, provide an efficacious treatment strategy, while minimizing the potential for NSAID-induced gastrointestinal and cardiovascular disturbances. Other potential "partners" for endocannabinoid modulatory agents include alpha(2)-adrenoceptor modulators, peroxisome proliferator-activated receptor alpha agonists and TRPV1 antagonists. An extension of the polypharmacological approach is to combine the desired pharmacological properties of the treatment within a single molecule. Hopefully, these approaches will yield novel analgesics that do not produce the psychotropic effects that limit the medicinal use of cannabis.

Fig. 1

Membrane bound CB₂ receptor (red) and cytoplasmic Gap43 (green) immunostaining in a human DRG small neuron in vitro. Bar=50 μm.

Fig. 2

Activation of cannabinoid CB₂ receptors suppresses the development and maintenance of inflammatory nociception in behavioral, electrophysiological and neurochemical studies. (a) AM1241 (33 μg/kg i.p.), administered locally in the inflamed paw, suppresses established carrageenan-evoked mechanical allodynia. Effects were blocked by the CB₂ antagonist SR144528 (33 μg/kg i.p.), but not by SR141716A (33 μg/kg i.p.). (b) AM1241 (330 μg/kg i.p.) induces a CB2-mediated suppression of the development of carrageenan-evoked (b) mechanical allodynia and (c) spinal Fos protein expression. (d) AM1241 (330 μg/kg, i.v.) suppressed total C-fiber-mediated neuronal excitability in spinal wide dynamic range neurons through a CB2-specific mechanism. AM1241 (330 μg/kg i.p.) also suppresses capsaicin-evoked (e) thermal hyperalgesia and (f) nocifensive behavior. (b–f) Effects were completely blocked by SR144528 (1 mg/kg), but not by SR141716A (1 mg/kg). Data (Mean+SEM). Sources: (a) Gutierrez et al. (2007); (b–c) Nackley et al. (2003a), (d) Nackley et al. (2004); (e–f) Hohmann et al. (2004).