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

Abstract

The endocannabinoid system consists of the cannabinoid (CB) receptors, CB1 and CB2, 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 CB1 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 CB2 receptor agonists. Selective CB2 agonists and peripherally restricted CB1 or CB1/CB2 dual agonists are being developed for the treatment of inflammatory and neuropathic pain, as they demonstrate efficacy in a range of pain models. CB2 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 CB2 receptors reported in human peripheral nerves have been seen after injury, particularly in painful neuromas. CB2 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 μ-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 α2-adrenoceptor modulators, peroxisome proliferator-activated receptor α 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.

Modulation of Peripheral Sensory Neurons by the Immune System: Implications for Pain Therapy

“…2-AG is metabolized to arachidonic acid and glycerol mainly by monoacylglycerol lipase, but FAAH is also involved (for review, see Di Marzo, 2009). Both receptors and their endogenous ligands are distributed across the key pain-modulating pathways of the nervous system in the brain, spinal cord and peripheral sensory neurons Anand et al, 2009;Di Marzo, 2009;Lever et al, 2009;Nyilas et al, 2009).…”

“…A peripherally restricted FAAH inhibitor elevated levels of anandamide in peripheral tissue, but not in the brain, and suppressed hypersensitivity in inflammatory and neuropathic pain in a CB1 receptor-dependent manner (Clapper et al, 2010). Peripheral CB2 receptors were also implied in alleviation of incisional, inflammatory and neuropathic pain (Kress and Kuner, 2009; for review, see Anand et al, 2009;Sagar et al, 2009;McDougall, 2011).…”

“…In most cases, cannabinoid effects seemed immunosuppressive, but stimulatory actions were also described (for review, see Tanasescu and Constantinescu, 2010). In vivo, exogenous cannabinoids produced anti-inflammatory actions (for review, see Anand et al, 2009;Tanasescu and Constantinescu, 2010). A possible relevance of such effects to pain was suggested in a study using palmitoylethanolamide, a fatty acid amide with cannabinomimetic properties.…”

“…This review will focus on the localization, trafficking, and function of peripheral opioid receptors, the production and release of opioid peptides in peripheral inflamed tissue, implications for analgesia and opioid tolerance, therapeutic issues in inflammatory diseases, and knowledge gaps defining future research directions. Because there is no evidence on the involvement of leukocyte-derived endocannabinoids in pain modulation, and peripheral analgesic effects of exogenously applied cannabinoids have been subject of numerous recent review articles (Akopian et al, 2009;Anand et al, 2009;Kress and Kuner, 2009;Sagar et al, 2009;McDougall, 2011), the cannabinoid system will be addressed only briefly.…”

The endocannabinoid system in pain and inflammation: Its relevance to rheumatic disease

“…Although originally described as being restricted to immune cells, evidence for CB2 receptor expression in neural cells involved in pain perception and modulation has emerged (29). In vitro studies show CB2 receptor expression in human DRG sensory neurons and nerve fibers within the synovium and digit skin (30). Recently, CB2 receptors were detected on β-endorphin-containing keratinocytes on the epidermis of rat hind paws.…”