Inhibition of visceral sensation by cannabinoids in the gastrointestinal tract

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Visceral sensation from the gastrointestinal (GI) tract begins with nerve terminals within the wall of the gut whose cell bodies reside in the dorsal root ganglion (DRG). While cannabinoids have been used for centuries to modulate sensation, it is unknown whether they modulate GI afferent nerves or if their effects on visceral sensation are mediated in the CNS. This is highly relevant as endogenous cannabinoids are synthesized in the GI tract and these may play an important a role in counterbalancing excitation of these nerves. Our long-term goal is to identify mechanisms how cannabinoid receptors, alone or in combination with signaling of other receptors, inhibit GI afferent nerves. Our preliminary data demonstrates that a cannabinoid 1 receptor (CB1R) reduces the sensory signaling of GI afferent nerves. Since opioids are the best characterized inhibitors of GI afferent nerves, we also investigated whether there was an interaction of cannabinoid and opioid receptors on these nerves. Interestingly, a combination of subthreshold concentrations of a CB1R agonist and a mu opioid receptor agonist inhibited these nerves. Based on these findings, our hypothesis is that intracellular signaling mechanisms of cannabinoid receptors converge with intracellular signaling mechanisms of opioid receptors to synergistically inhibit colonic afferent nerves. To test this hypothesis, we have two objectives: 1)Characterize the inhibitory signaling mechanisms of cannabinoid receptors on extrinsic colonic afferent nerves. Here we will employ ex vivo extracellular recordings of colon afferent nerves and patch clamp recordings of colon projecting DRG neurons to further explore the role of CB1R and CB2R on these nerves. We will use pharmacological and molecular approaches to investigate which intracellular signaling pathway(s) is involved in their inhibitory effect. 2)Determine signaling mechanisms necessary for synergistic inhibition of colonic afferent nerves following simultaneous activation of cannabinoid and opioid receptors. Here we will use electrophysiological and immunohistochemical techniques to examine the co-expression of the receptors on colon afferent nerves. We will use pharmacological and molecular approaches to elucidate intracellular pathway(s) necessary for synergism following simultaneous activation of the receptors. These studies will characterize cannabinoid receptor signaling on GI afferent nerves as well as advance our understanding of how cannabinoid and opioid receptors interact to modulate visceral sensation. Furthermore, our findings may spark commercial opportunities to develop therapeutics that specifically target GI afferent nerves. In addition, this research program will train multiple undergraduate students and graduate students, and a post-doctoral fellow. The skills obtained during their training will be transferable to employment to any career they pursue enabling them to contribute to Canadian economic development.