Disruption of opioid and mesolimbic dopamine dynamics and behavior upon intranasal delivery of opioids in mice

Abstract

The endogenous opioid system, consisting of mu, delta, and kappa opioid receptors, along with naturally occurring peptides, is central for regulating reward processing, mood, motivation, and social attachment. Endogenous opioids, as well as opioid drugs that are administered clinically or are misused/abused, are potent modulators of several neurotransmitter systems in the brain, including dopamine (DA). Since the opioid system is dysregulated in neuropsychiatric conditions, and opioids are prevalently misused/abused to achieve altered affective and cognitive states, the understanding of the mechanisms of action of opioids is highly significant. Unfortunately, there is no pre-clinical approach for understanding the actions of intranasally (IN) administered opioids, a common route of administration by both individuals with opioid use disorder and a route used clinically to achieve reversal of opioid overdose. Here we combined reliable and precise delivery of opioids into the nasal cavity of mice together with measures of opioid and DA dynamics in the nucleus accumbens (NAc) with fiber photometry, or, with measures of behaviors known impacted by opioids following other routes of administration, including respiration, to demonstrate the outcomes of IN opioids in mice. We uncovered a prompt and prolonged increase in mesolimbic DA by both IN morphine and fentanyl and the restoration of DA to baseline levels by subsequent IN opioid receptor antagonism with naloxone. Simultaneously, IN morphine and fentanyl each resulted in a short-lasting increase in NAc opioid dynamics. Next, in separate mice, we found that IN opioids elicit rapid canonical opioid-induced behaviors, including respiratory depression, which were rapidly reversed by IN naloxone. Overall, this work establishes a sensitive approach for evaluating the neural circuitry underlying opioid use disorder in a manner which recapitulates IN opioid use with ecological validity. Moreover, our findings point towards a likely important role for mesolimbic DA in mediating opioid overdose reversal.