Different Classes of CB2 Ligands Potentially Useful in the Treatment of Pain

Abstract

The search of new drugs and targets to treat the pain is an intriguing challenge both for several companies and researchers from academia. In this context, since the modulation of the endocannabinoid system with the non selective phytocannabinoid Δ9-THC produces analgesia and potentiates opioid analgesia in animal models, CB2 ligands studies aimed to explore the involvement of endocannabinoid system in management of pain were started. Several selective CB2 receptor agonists exhibited analgesic activity in preclinical models of acute, inflammatory and neuropathic pain, therefore this class of modulators could be useful as analgesic agents for pain, migraine, inflammation and osteoarthritis. This review is an update of our previously manuscript "A survey of recent patents on CB2 agonists in the management of pain" and provides an overview of patents and advances in CB2 agonist studies in the treatment of pain.

CB2Cannabinoid Receptors as a Therapeutic Target—What Does the Future Hold?

“…These findings offered the possibility of producing significant analgesia through the endogenous cannabinoid system in the absence of CB 1 -mediated psychoactivity. Subsequent work by a number of groups has confirmed and extended these studies with a variety of structurally distinct CB 2 agonists (Murineddu et al, 2013). Generally, the field has moved away from AM1241, as AM1241 appears to engage a unique endogenous opioid-mediated component for its analgesia (Ibrahim et al, 2005;Whiteside et al, 2005); its enantiomers have different actions and its efficacy is species-dependent (Bingham et al, 2007); and it is a low-efficacy agonist, as it exhibits protean agonism (Yao et al, 2006).…”

The endocannabinoid system and neuropathic pain

“…Thus, recent studies have revealed that non selective cannabinoid agonists reduce the cognitive impairment associated to diabetic neuropathy [24] and selective CB2R agonists reduced the depressive-like behavior [43] and alleviate spontaneous neuropathic pain in an operant model of selfmedication [39]. Interestingly, these CB2R agonists are devoid of the cannabimimetic effects of CB1R agonists [74].…”

“…New strategies for using cannabinoids more efficiently include the selective targeting of CB1R and CB2R, the inhibition of endogenous cannabinoid uptake and metabolism in selected tissues, the harnessing of cannabinoid-opioid synergies, and the delivery of cannabinoids by improved strategies [118]. Indeed, several selective CB2R agonists and MAGL/FAAH inhibitors have shown promising analgesic activity in preclinical models of neuropathic pain [46,74]. However, these promising results must be confirmed in more relevant animal models of neuropathic pain with experimental conditions closer to the clinical conditions.…”

Phosphorylation of extracellular signal-regulated kinase as a biomarker for cannabinoid receptor 2 activation

“…Although both CB1 and CB2 receptors have been detected in leukocyte mediators of inflammation, CB2 is believed to play a more important role and appears to be the key mediator of cannabinoid regulation of inflammation and immune functions. CB2R is primarily expressed in peripheral organs and especially in immune cells [ 2 , 3 ]: compared to CB1R, it shows 10- to 100-fold higher expression in cells of the immune system such as B and T lymphocytes, monocytes, and macrophages [4] . CB2R plays an important role in regulating inflammatory responses under both physiological and pathological conditions, and small-molecule modulators of CB2R including agonists have been developed for the treatment of various inflammatory diseases [ 5 , 6 ].…”