575. ALLEVIATING OPIOID WITHDRAWAL: FROM RODENTS TO HUMAN CLINICAL TRIAL

Abstract Background People on long-term opioid medications can experience withdrawal symptoms when attempting to reduce or stop their use. Withdrawal is a major problem in the opioid crisis because it impacts people on chronic opioids, including those who are prescribed opioids for therapeutic control of pain or those who are misusing or abusing opioids. Interventions that reduce withdrawal can break the cycle of opioid use. Our team uncovered a mechanistic explanation for the aberrant autonomic output, which underlies many of the debilitating withdrawal symptoms. The locus coeruleus (LC) is a key autonomic centre with projections originating from this site containing norepinephrine that send important inputs to the spinal cord. Both the LC and spinal cord are implicated in withdrawal, but the interaction between these anatomical sites for opioid action is not well defined. Aims & Objectives To determine how the locus coeruleus (LC) contributes to opioid withdrawal. Method The study uses a combination of advanced behavioral, cellular, chemogenetic, and electrophysiological techniques to explore how a specific top-down LC to spinal circuit contributes to opioid withdrawal. Results We found that during opioid withdrawal spinally-projecting LC neurons are hyperexcitable, and that cerebral spinal fluid levels of noradrenaline were significantly elevated. This hyperexcitability was dependent on pannexin-1 (Panx1) channels expressed on microglia, which are immune cells in the central nervous system. Pharmacological inhibition or genetic knockdown of microglial Panx1 reduced LC neuron hyperactivity, suppressed noradrenaline release in the cerebral spinal fluid, and attenuated withdrawal behaviours. Inhibition of Pannexin-1 channels also reduced affective measures of opioid withdrawal: conditioned place aversion and cue-induced reinstatement of opioid seeking. Probenecid, a broad spectrum Panx1 blocker, that effectively reduces withdrawal in rodent models is now being tested in a human Phase ​2a trial for opioid withdrawal. Discussion & Conclusions The findings establish that aberrant spinally projecting LC output critically underlies opioid withdrawal and that blocking Panx1 channels is a potential therapeutic strategy for alleviating withdrawal symptoms.