Cannabinoid Receptor Type 1 and Its Role as an Analgesic: An Opioid Alternative?

Abstract

Understanding the intricacies of how the body regulates pain is fundamental to develop rational strategies to combat the growing prevalence of chronic pain states, opioid dependency, and the resulting increased financial burden to the medical care system. Pain is the most prominent reason why Americans seek medical attention and extensive literature has identified the importance of the endocannabinoid pathway in controlling pain. Endocannabinoid signaling machinery operates in a synapse-specific manner, and its modulation offers new therapeutic opportunities for the selective control of excessive neuronal activity in several pain conditions (acute, inflammatory, chronic, and neuropathic). Cannabinoids have a long history of medicinal use and their analgesic properties are well documented; however, there are major impediments to understanding cannabinoid pain modulation. One major issue is the presence of psychotropic side effects associated with Δ9tetrahydrocannabinoil (THC) or synthetic derivatives, which puts an emphatic brake on their use. This dose-limiting effect lends to the idea that the appropriate degree of analgesia cannot be reached before the presence of severe side effects. Animal studies have shown that the psychotropic effects are mediated via brain cannabinoid type 1 (CB1) receptors, while analgesic activity in chronic pain states may be mediated via CB1R action in the spinal cord, brainstem, peripheral sensory neurons, or immune cells. The development of appropriate therapies is incumbent on our understanding of the role of peripheral versus central endocannabinoid-driven analgesia. Recent physiological, pharmacological, and anatomical studies provide evidence that one of the main roles of the endocannabinoid system is the regulation of gamma-aminobutyric acid (GABA) and/or glutamate release. This article will review this evidence in the context of its implications for pain. We first provide a brief overview of CB1R's role in the regulation of nociception, followed by a review of the evidence that the peripheral endocannabinoid system modulates nociception. We then look in detail at regulation of central-mediated analgesia, followed up with evidence that cannabinoid-mediated modulation of pain involves modulation of GABAergic and glutamatergic neurotransmission in key brain regions. Finally, we discuss cannabinoid action on non-neuronal cells in the context of inflammation and direct modulation of neurons. This work stands to reveal long-standing controversies in the cannabinoid analgesia area *

The Neuroimmunology of Chronic Pain: From Rodents to Humans

“…Cannabinoid receptor Type 1 (CB1R) as a neuroimmune therapeutic target for chronic pain Preclinical studies in the neuroimmunology of chronic pain have revealed numerous potential therapeutic targets. Among these, CB1R has been identified as a viable candidate in controlling pain and inflammation (Kunos et al, 2009;Milligan et al, 2020). Global CB1R KO studies have demonstrated the necessity of CB1R action for both endogenous and therapeutically induced pain inhibition (Sideris et al, 2016;Bajic et al, 2018).…”

Endocannabinoidome and its role in neurological disorders-A comprehensive update of existing literature

“…Neuropathic pain: CB1 has an important analgesic property which can be an alternative to opioids in treating chronic neuropathic pain [179]. Sharon et al has reported cannabinoids for otherwise unresponsive pain but care should be taken in frail clinical populations [180].…”

Cannabinoid Receptors and Their Relationship With Chronic Pain: A Narrative Review

“…Bringing it down to a more molecular level, studies identified the action through cannabinoid receptors being activated via G(i/o) proteins, negatively modulate cyclic adenosine monophosphate (AMP) levels, and activated inward rectifying K(+) channels [13]. The G protein-coupled receptors, when activated, send signals downwards and may also have a role in the regulation of gamma-aminobutyric acid (GABA) and glutamate release [1]. Both these targets are known to affect the pain pathway.…”

“…Pain is the most sought out reason why Americans seek medical attention, and comprehensive literature has identified the relevance of the endocannabinoid pathway in controlling pain [1]. The activation of cannabinoid receptors is believed to have antinociceptive effects in controlling the human perception of pain.…”