Peripheral Sensory Neuron CB2 Cannabinoid Receptors are Necessary for Both CB2-Mediated Antinociceptive Efficacy and Sparing of Morphine Tolerance in a Mouse Model of
Anti-retroviral Induced Neuropathic Pain
Lawrence M. Carey1,2, Zhili Xu2, Gabriela Rajic2, Alexandros Makriyannis3, Julian Romero4, Cecilia Hillard5, Ken Mackie1,2,6 and Andrea G. Hohmann1,2,6*
1Program in Neuroscience, Indiana University, Bloomington, IN, 2Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, 3Center for Drug Discovery, Northeastern University, Boston, MA, 4Faculty of Experimental Sciences, Universidad Francisco de Vitoria, Madrid, Spain, 5Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, 6Gill Center for Biomolecular Science, Indiana University, Bloomington, IN
Painful peripheral neuropathy is the most common neurological complication associated with human immune deficiency virus (HIV) infection. Currently available treatments fail to provide adequate symptom relief, indicating the need for novel treatment strategies. To address this gap in knowledge, we characterized the impact of cannabinoid CB2 agonists, which lack psychoactivity associated with central CB1 activation, on antiretroviral-induced neuropathic nociception and identified cell types expressing CB2 that mediate the antinociceptive efficacy of CB2 agonists. Two structurally distinct CB2 agonists (AM1710 and LY2828360) alleviated antiretroviral-induced neuropathic pain, benefits which were absent in CB2 knockout mice. Conditional deletion of CB2 from peripheral sensory neurons eliminated the antinociceptive efficacy of CB2 agonists. We also asked whether LY2828360 treatment could reverse established morphine tolerance in the ddC-induced neuropathy model and whether CB2 expression on peripheral sensory neurons is necessary for sparing of morphine tolerance by LY2828360. The present studies suggest that CB2 activation may alleviate HIV-associated antiretroviral neuropathy and identify a previously unreported mechanism through which CB2 activation produces antinociceptive efficacy. Our results also provide the first evidence that a CB2 agonist can reverse established morphine tolerance and demonstrate that CB2 localized to peripheral sensory neurons mediates the opioid tolerance sparing efficacy of CB2 agonists.
This work was supported by National Institute on Drug Abuse Grants DA047858, DA041229 (A.G.H. and K.M.), and DA042584 (A.G.H.), National Cancer Institute Grant CA200417 (A.G.H.), an Indiana Addiction Grand Challenge Grant (A.G.H.), the Research and Education Component of the Advancing a Healthier Wisconsin Endowment at the Medical College of Wisconsin (C.J.H) and the Ministerio de Economía y Competitividad (SAF 2016-75959-R and SAF PID2019-108992RB-I00 to JR). L.M.C. was supported by National Institute on Drug Abuse T32 training grant DA024628 and the Harlan Scholars Research Program.