Inhibition of dorsal raphe GABAergic neurons blocks hyperalgesia during heroin withdrawal

Abstract

Opioid withdrawal signs, such as hyperalgesia, are manifestations of opioid use disorder that may contribute to opioid seeking and taking. We have previously identified an association between dorsal raphe (DR) neurons and the expression of hyperalgesia during spontaneous heroin withdrawal. Here, we found that chemogenetic inhibition of DR neurons decreased hyperalgesia during spontaneous heroin withdrawal in male and female C57/B6 mice. By neuroanatomy, we identified three major subtypes of DR neurons expressing μ-opioid receptors (MOR) that were activated in hyperalgesia during spontaneous withdrawal, those expressing vesicular GABA transporter (VGaT), glutamate transporter 3 (VGluT3), or co-expressing VGluT3 and tryptophan hydroxylase (TPH). In contrast, we identified a small population of DR-MOR neurons expressing solely TPH, which were not activated in hyperalgesia during spontaneous withdrawal. Collectively, these findings indicate a role of the DR in hyperalgesia during spontaneous heroin withdrawal mediated, in part, by the activation of local MOR-GABAergic, MOR-glutamatergic and MOR-co-releasing glutamatergic-serotonergic neurons. We found that specific chemogenetic inhibition of DR-VGaT neurons blocked hyperalgesia during spontaneous heroin withdrawal in male and female mice. Collectively, these findings indicate that DR-GABAergic neurons play a role in the expression of hyperalgesia during spontaneous heroin withdrawal.

A novel tramadol–polycaprolactone implant could palliate heroin conditioned place preference and withdrawal in rats: behavioral and neurochemical study

“…One-way analysis of variance followed by Tukey's test of significance at *P < 0.05; **P < 0.01; ****P < 0.0001 compared with Her + Veh + Nalox. (Alvarez-Bagnarol et al, 2023). It plays a key role in heroin self-administration studies and cue-induced reinstatement of a variety of substances of reward-related disorders (Grimm et al, 2007;Burattini et al, 2008;Liu et al, 2009;Theberge et al, 2012).…”

“…The endogenous opioid system is considered an important target for the management of drug abuse, especially acting on MOR (Kreek et al ., 2002). The MOR mRNA is expressed in different neuron subpopulations that release 5-HT, GABA, or glutamate (Alvarez-Bagnarol et al ., 2023). It plays a key role in heroin self-administration studies and cue-induced reinstatement of a variety of substances of reward-related disorders (Grimm et al ., 2007; Burattini et al ., 2008; Liu et al ., 2009; Theberge et al ., 2012).…”

“…Tramadol was reported to be a 5-HT reuptake inhibitor (Driessen and Reimann, 1992;Frink et al, 1996) and is associated with enhanced serotonergic transmission (Bloms-Funke et al, 2011). Previous studies of morphine-dependent rats described 5-HT turnover increases after spontaneous withdrawal, and a decrease in extracellular levels after naltrexone precipitated withdrawal (Alvarez-Bagnarol et al, 2023). It is known that serotonin reuptake inhibitors administration during withdrawal symptoms reduces physical and negative emotional symptoms (Goeldner et al, 2011).…”