Chronic THC vapor rescues inflammation-related thermal hyperalgesia and causes cell type-specific modifications in vlPAG neurons

Abstract

AbstractTo reduce reliance on opioids for the treatment of pain in the clinic, ongoing work is testing the utility of cannabinoid drugs as a potential alternative for treatment of chronic pain and/or as a strategy for reducing opioid drug dosage and duration of treatment (i.e., so-called opioid-sparing effects). Previous preclinical work has shown robust anti-hyperalgesic effects of systemic THC and acute anti-hyperalgesic effects of vaporized THC. Here, we used a vapor inhalation model in rats to test chronic THC vapor inhalation effects on thermal nociception and mechanical sensitivity, as well as midbrain (i.e., periaqueductal gray [PAG]) neuronal function, in adult male rats with chronic inflammatory pain. We report that chronic THC vapor inhalation produces a robust anti-hyperalgesic effect in rats with chronic inflammatory pain, and that this effect persists 24 hours after cessation of THC exposure. We demonstrate that chronic THC vapor inhalation also modulates intrinsic and synaptic properties of ventrolateral PAG (vlPAG) neurons, including reductions in action potential firing rate and reductions in spontaneous inhibitory synaptic transmission, and that these effects occur specifically in neurons that respond to current input with a delayed firing phenotype. Finally, we show that the suppressive effect of the bath-applied mu-opioid receptor (MOR) agonist DAMGO on synaptic inhibition in the vlPAG is enhanced in slices taken from rats with a history of chronic THC vapor inhalation. Collectively, these data show that chronic THC vapor inhalation produces lasting attenuation of thermal hyperalgesia and reduces synaptic inhibition in the vlPAG of rats with chronic inflammatory pain.Significance StatementMany adults in the U.S. with pain self-medicate with THC and cannabis, and many cannabis users are increasingly using e-cigarette type devices filled with cannabis extracts to self-administer THC and other constituents of the marijuana plant. Until recently, most rodent studies of THC effects on brain and behavior have not used vapor inhalation techniques. Here, we designed a series of studies to test the effect of chronic THC vapor inhalation on pain-related behaviors and midbrain neural circuit function in adult male Wistar rats. We hypothesized that chronic THC vapor would have anti-hyperalgesic effects in rats with chronic inflammatory pain, and that it would produce disinhibition of midbrain pain modulation neurons.