Peripherally Restricted Cannabinoids for the Treatment of Pain

Abstract

The use of cannabinoids for the treatment of chronic diseases has increased in the United States, with 23 states having legalized the use of marijuana. Although currently available cannabinoid compounds have shown effectiveness in relieving symptoms associated with numerous diseases, the use of cannabis or cannabinoids is still controversial mostly due to their psychotropic effects (e.g., euphoria, laughter) or central nervous system (CNS)-related undesired effects (e.g., tolerance, dependence). A potential strategy to use cannabinoids for medical conditions without inducing psychotropic or CNS-related undesired effects is to avoid their actions in the CNS. This approach could be beneficial for conditions with prominent peripheral pathophysiologic mechanisms (e.g., painful diabetic neuropathy, chemotherapy-induced neuropathy). In this article, we discuss the scientific evidence to target the peripheral cannabinoid system as an alternative to cannabis use for medical purposes, and we review the available literature to determine the pros and cons of potential strategies that can be used to this end.

Delta‐9‐tetrahydrocannabinol decreases masticatory muscle sensitization in female rats through peripheral cannabinoid receptor activation

“…In the electrophysiology experiments, THC increased the mechanical thresholds of mechanoreceptors that innervate the masseter muscle through peripheral CB1 receptor activation. These results are consistent with earlier studies which found that local administration of THC reduced sensitization in muscle pain conditions (Johanek et al, 2001;Yu et al, 2010;Bagues et al, 2014;Romero-Sandoval et al, 2015). Our results suggest that peripheral application of cannabinoids may be effective in the treatment of muscle pain disorders and may be a more desirable strategy than systemic administration due to a lower potential for CNS side effects.…”

“…One way to circumvent these CNS side effects is to use a low dose, local tissue administration of these drugs to target peripheral receptors. In this regard, peripherally administered cannabinoids have been proposed as one potential solution to reduce the CNS side effects associated with systemic administration of these agents (Romero‐Sandoval et al., ). In this study, expression of both CB1 and CB2 receptors was observed in trigeminal ganglion neurons innervating the masseter muscle, providing evidence that these receptors can be targeted for masticatory muscle pain.…”

“…For example, inhibitors of fatty acid amide hydrolase, the primary deactivating enzyme for the endocannabinoid anandamide, have been investigated as potential therapeutic agents for chronic pain, however, they have yet to be translated to clinical application (Krustev et al, 2014;Lodola et al, 2015). Recent studies suggest that peripheral application of cannabinoids could be an effective strategy for analgesia without central side effects (Johanek et al, 2001;Yu et al, 2010;Bagues et al, 2014;Romero-Sandoval et al, 2015).…”

Cannabis for Chronic Pain: Challenges and Considerations

“…CB1 receptors are most widely expressed in the central and peripheral nervous systems, while CB2 receptors are mostly expressed in immune cells and therefore in the periphery. 7,8 As a result, the mechanism of action of cannabis seems to be through THC via neuronal actions (centrally and peripherally). These actions are responsible not only for the analgesic effects of cannabis but also for its psychotropic (i.e., euphoric or "high") effects.…”

Cannabinoids: Drug or Medication?

“…Alternative perspectives for specific medical conditions are oriented toward cannabinoid antagonists that will only act on the periphery without CNS related adverse effects. Such compounds are being developed to treat pain (see [246]) and may also be useful for obesity and metabolic disorder, as preclinical studies have demonstrated decreased food intake using LH-21, an antagonist with a poor penetration rate into the central nervous system [247]. Likewise, peripheral antagonism may be beneficial for other pathologies with noticeable peripheral pathophysiologic mechanisms including gastrointestinal, liver, pancreatic, or coronary artery diseases ( [240] and references therein).…”