The Endocanbinoid System and CBD Receptors
The endogenous cannabinoid system has been described as “an ancient lipid signaling network which in mammals modulates neuronal functions, inflammatory processes, and is involved in the etiology of certain human lifestyle diseases, such as Crohn’s disease, atherosclerosis and osteoarthritis. The system is able to downregulate stress-related signals that lead to chronic inflammation and certain types of pain, but it is also involved in causing inflammation-associated symptoms, depending on the physiological context.
CB1 Receptors
The CB1 receptor has been cloned from humans. Activation of CB1 receptors leads to dose-dependent and stereo-selective inhibition of adenylate cyclase activity, thus affecting memory, perception, and movement. The CB1 receptor appears to be responsible for the mood-enhancing effects of Cannabis as well as negative, dysphoria-inducing, and frank psychotomimetic effects in susceptible individuals. CB1 receptor distribution has been well characterized in the human brain. The receptors are expressed in high abundance in the hippocampus and associational cortical regions, the cerebellum, and the basal ganglia. This widespread distribution in the brain matches well with the known pharmacodynamic effects of cannabinoids. In contrast, binding is sparse or absent from the brain stem, medulla, and thalamus. The paucity of CB1 receptors in these areas helps explain the absence of life-threatening effects on vital physiological functions associated with extremely high doses of cannabinoids. Besides the brain, the CB1 receptor occurs in the testis, and presynaptically on sympathetic nerve terminals. CB1 receptor mRNA has been identified in the adrenal gland, heart, lung, prostrate, bone marrow, thymus, and tonsils.
CB2 Receptors
Although CB1 and CB2 receptors share considerable structural similarities, their distribution and activity diverge. Among other actions, including pain modulation, CB2 receptors are thought to serve an important role in immune function and inflammation. There is ample evidence that CB2 receptor activation reduces nociception in a variety of preclinical models, including those involving tactile and thermal allodynia, mechanical and thermal hyperalgesia, and writhing. With regard to their role in modulating neuropathic pain, the presence of CB2 receptors on microglia within the nervous system may explain the putative benefits of cannabinoids in reducing cytokine-mediated neuroinflammation. CB1 and CB2 receptors inhibit adenylate cyclase via interactions at the G-protein complex. However, their activation and consequent inhibition of various ion channels differs. The key point is that differential binding of CB1 or CB2 receptors, either separately or in combination by their respective endogenous or exogenous ligands, leads to varied physiological effects, mediated via several neurotransmitters, including acetylcholine, glutamate, and dopamine.
CBD and Pain
Evidence continues to accumulate suggesting that cannabinoids can impact normal inhibitory pathways and pathophysiological processes influencing nociception in humans. When cannabinoids do have an analgesic effect, it is more likely to occur in hyperalgesic and inflammatory states. Clinical trials lasting from days to months, involving more than 1,000 patients, have shown efficacy in different categories of chronic pain conditions, but the vast majority of controlled trials have involved patients with chronic neuropathic pain.