Sustained fentanyl exposure inhibits neuronal activity in dissociated striatal neuronal-glial co-cultures through actions independent of opioid receptors.

Abstract

Besides having high potency and efficacy at the µ- (MOR) and other opioid receptor types, fentanyl has some affinity for some adrenergic receptor types, which may underlie its unique pathophysiological differences from typical opioids. To better understand the unique actions of fentanyl, we assessed the extent to which fentanyl alters striatal medium spiny neuronal (MSNs) activity via opioid or α1 adrenoceptors in dopamine type 1 or type 2 receptor- (D1 or D2) -expressing MSNs. In neuronal and mixed-glial co-cultures from the striatum, acute fentanyl (100 nM) exposure decreased the frequency of spontaneous action potentials. Overnight exposure of co-cultures to 100 nM fentanyl severely reduced the proportion of MSNs with spontaneous action potentials, which was unaffected by co-exposure to the opioid receptor antagonist naloxone (10 µM), but fully negated by co-administering the pan-α1 adrenoceptor inverse agonist prazosin (100 nM) and partially reversed by the selective α1A/C adrenoceptor antagonist RS 100329 (300 nM). Acute fentanyl (100 nM) exposure modestly reduced the frequency of action potentials and caused firing rate adaptations in D2, but not D1, MSNs. Prolonged (2-5 h) fentanyl (100 nM) application dramatically attenuated firing rates in both D1 and D2 MSNs. To identify possible cellular sites of α1 adrenoceptor action, α1 adrenoceptors were localized in subpopulations of striatal astroglia and neurons by immunocytochemistry, and Adra1a mRNA by in situ hybridization in astrocytes. Thus, sustained fentanyl exposure can inhibit striatal MSN activity via a non-opioid receptor-dependent pathway, that may be modulated via complex actions in α1 adrenoceptor-expressing striatal neurons and/or glia.