Targeting cannabinoid agonists for inflammatory and neuropathic pain

Abstract

The cannabinoid receptors CB(1) and CB(2) are class A G-protein-coupled receptors. It is well known that cannabinoid receptor agonists produce relief of pain in a variety of animal models by interacting with cannabinoid receptors. CB(1) receptors are located centrally and peripherally, whereas CB(2) receptors are expressed primarily on immune cells and tissues. A large body of preclinical data supports the hypothesis that either CB(2)-selective agonists or CB(1) agonists acting at peripheral sites, or with limited CNS exposure, will inhibit pain and neuroinflammation without side effects within the CNS. There has been a growing interest in developing cannabinoid agonists. Many new cannabinoid ligands have been synthesized and studied covering a wide variety of novel structural scaffolds. This review focuses on the present development of cannabinoid agonists with an emphasis on selective CB(2) agonists and peripherally restricted CB(1) or CB(1)/CB(2) dual agonists for treatment of inflammatory and neuropathic pain.

Hemopressin is an inverse agonist of CB 1 cannabinoid receptors

“…Because a large body of evidence has clearly demonstrated the antinociceptive action of CB 1 receptor agonists, these results are paradoxical (in that receptor antagonists also have antinociceptive effects; reviewed in refs. [23][24][25][26]. A possible explanation for these paradoxical in vivo effects (by CB 1 agonists and antagonists) could be that endocannabinoids activate distinct signal transduction pathways under different paradigms used to measure pain leading to distinct and opposing effects.…”

Role of Endocannabinoids in Neuron-Glial Crosstalk

“…CB1 receptor mediated analgesia is associated with adverse psychoactive effects such as sedation, dependence, cognitive impairment and psychotic-like behaviour [50,51], due to the overall activation of this ubiquitous receptor. However, CB2 receptor stimulation is also effective in alleviating inflammatory [52][53][54]10] and neuropathic pain [25,[55][56][57][58][59]. Intriguingly, the CB2-mediated antinociceptive effects seem devoid of any central action (which are CB1 receptor-mediated), and are likely mediated by several mechanisms, and peripheral sites of action of CB2 agonists in both inflammatory and neuropathic pain models have been recognized [52,53,55,56].…”

Pain-related behaviors and neurochemical alterations in mice expressing sickle hemoglobin: modulation by cannabinoids

“…[9][10][11][12][13] Inhaled or systemically injected cannabinoids are effective in treating pain in HIV/AIDS and multiple sclerosis and breakthrough pain in cancer. 9,13,14 Activation of peripheral cannabinoid receptors attenuates hyperalgesia in inflammation and cancer.…”