LIN Seminar: Harnessing the Therapeutic Potential of the Endocannabinoid Signaling System to Suppress Neuropathic Pain by Andrea Hohmann, Indiana University Bloomington

Speaker: Andrea Hohmann, Ph.D.

Linda and Jack Gill Chair of Neuroscience and Professor

Dept. of Psychological & Brain Sciences

Indiana University Bloomington

Faculty Host: Amynah Pradhan

Abstract: 

A need for pharmacotherapies for pain that are safe, effective and non-addicting is widely recognized. Here, I will discuss therapeutic strategies that suppress neuropathic pain while limiting unwanted side effects by engaging the endocannabinoid signaling system. The endocannabinoid system consists of cannabinoid receptors (CB1, CB2), endocannabinoids (2-AG, anandamide) and the enzymes (FAAH, MGL) which control the synthesis and degradation of endocannabinoids.  CB1 receptors are densely expressed in the central nervous system (CNS). By contrast, CB2 receptors are mainly expressed in the periphery, in immune cells, but can be upregulated in the CNS in response to inflammation and injury. Activation of CB1 receptors produces many desirable therapeutic properties but engaging these receptors also produces unwanted side effects including tolerance, psychoactivity and abuse liability. Preclinical research in my laboratory has, therefore, validated distinct approaches aimed at activating an array of targets within the endocannabinoid system to suppress pathological pain without the unwanted side effects associated with direct acting cannabinoid CB1 agonists. Classical cannabinoid agonists, such as D⁹-tetrahydrocannabinol (THC), the major psychoactive ingredient in cannabis, suppresses neuropathic pain in rodent models, but tolerance develops with repeated administration and other unwanted side effects (e.g. signs of physical dependence) are also observed. Our studies suggest that CB2 receptors can be targeted to suppress specific neuropathic pain states without producing tolerance, physical dependence or other unwanted CB1-mediated side effects. In our studies, a functionally-biased CB2 agonist suppressed neuropathic pain in mice with sustained efficacy and also attenuated unwanted effects of opioid analgesics, such as tolerance and physical dependence. The recent discovery of an allosteric binding site on the CB1 receptor, which is distinct from the site that binds direct acting cannabinoid agonists, has prompted research efforts aimed at exploiting the therapeutic potential of indirectly enhancing endocannabinoid-mediated signal transduction at CB1 receptors through allosteric modulation. This approach offers potential to produce a more circumscribed and beneficial spectrum of biological effects compared to direct activation of CB1 receptors with classical cannabinoid agonists such as THC. To this end, CB1 positive allosteric modulators (PAMs) show considerable promise for suppressing inflammatory and neuropathic pain without producing tolerance, physical dependence or unwanted side effects associated with either orthosteric CB1 agonists or inhibitors of the 2-AG deactivating enzyme monoacylglycerol lipase. CB1 PAMs also offer the potential to more specifically enhance the signaling of endocannabinoids compared to inhibitors of endocannabinid deactivation. Finally, our studies raise the possibility that effective pain suppression may also be achieved by engaging the endocannabinoid signaling system through both pharmacological and nonpharmacological environmental approaches.