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Inhaled Cannabis Suppresses Chemotherapy-Induced Neuropathic Nociception by Decoupling the Raphe Nucleus: A

Ilayda Alkislar¹, Alison R Miller¹, Andrea G Hohmann²

¹Center for Translational Neuroimaging, Northeastern University, Boston, Massachusetts.

Biological Psychiatry. Cognitive Neuroscience and Neuroimaging

|February 24, 2021

Abstract

Background:

Efficacy of inhaled cannabis for treating pain is controversial. Effective treatment for chemotherapy-induced neuropathy represents an unmet medical need. We hypothesized that cannabis reduces neuropathic pain by reducing functional coupling in the raphe nuclei.

Methods:

We assessed the impact of inhalation of vaporized cannabis plant (containing 10.3% Δ⁹-tetrahydrocannabinol/0.05% cannabidiol) or placebo cannabis on brain resting-state blood oxygen level-dependent functional connectivity and pain behavior induced by paclitaxel in rats. Rats received paclitaxel to produce chemotherapy-induced peripheral neuropathy or its vehicle. Behavioral and imaging experiments were performed after neuropathy was established and stable. Images were registered to, and analyzed using, a 3D magnetic resonance imaging rat atlas providing site-specific data on more than 168 different brain areas.

Results:

Prior to vaporization, paclitaxel produced cold allodynia. Inhaled vaporized cannabis increased cold withdrawal latencies relative to prevaporization or placebo cannabis, consistent with Δ⁹-tetrahydrocannabinol-induced antinociception. In paclitaxel-treated rats, the midbrain serotonergic system, comprising the dorsal and median raphe, showed hyperconnectivity to cortical, brainstem, and hippocampal areas, consistent with nociceptive processing. Inhalation of vaporized cannabis uncoupled paclitaxel-induced hyperconnectivity patterns. No such changes in connectivity or cold responsiveness were observed following placebo cannabis vaporization.

Conclusions:

Inhaled vaporized cannabis plant uncoupled brain resting-state connectivity in the raphe nuclei, normalizing paclitaxel-induced hyperconnectivity to levels observed in vehicle-treated rats. Inhaled vaporized cannabis produced antinociception in both paclitaxel- and vehicle-treated rats. Our study elucidates neural circuitry implicated in the therapeutic effects of Δ⁹-tetrahydrocannabinol and supports a role for functional imaging studies in animals in guiding indications for future clinical trials.

Keywords:

Cold allodynia Hyperconnectivity Paclitaxel Phytocannabinoids Resting-state BOLD functional connectivity Serotonin Tetrahydrocannabinol Vaporized marijuana plant

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