Mu Opioid Receptors in Gamma-Aminobutyric Acidergic Forebrain Neurons Moderate Motivation for Heroin and Palatable Food

Abstract

BACKGROUND Mu opioid receptors (MORs) are central to pain control, drug reward and addictive behaviors, but underlying circuit mechanisms have been poorly explored by genetic approaches. Here we investigate the contribution of MORs expressed in GABAergic forebrain neurons to major biological effects of opiates, and also challenge the canonical disinhibition model of opiate reward. METHODS We used Dlx5/6-mediated recombination to create conditional Oprm1 mice in GABAergic forebrain neurons. We characterized the genetic deletion by histology, electrophysiology and microdialysis, probed neuronal activation by c-Fos immunohistochemistry and resting state-functional magnetic resonance imaging, and investigated main behavioral responses to opiates, including motivation to obtain heroin and palatable food. RESULTS Mutant mice showed MOR transcript deletion mainly in the striatum. In the ventral tegmental area (VTA), local MOR activity was intact, and reduced activity was only observed at the level of striatonigral afferents. Heroin-induced neuronal activation was modified at both sites, and whole-brain functional networks were altered in live animals. Morphine analgesia was not altered, neither was physical dependence to chronic morphine. In contrast, locomotor effects of heroin were abolished, and heroin-induced catalepsy was increased. Place preference to heroin was not modified, but remarkably, motivation to obtain heroin and palatable food was enhanced in operant self-administration procedures. CONCLUSIONS Our study reveals dissociable MOR functions across mesocorticolimbic networks. Thus beyond a well-established role in reward processing, operating at the level of local VTA neurons, MORs also moderate motivation for appetitive stimuli within forebrain circuits that drive motivated behaviors.

Mu and delta opioid receptors play opposite nociceptive and behavioural roles on nerve‐injured mice

“…In this case, increased thermosensation was partly reproduced when MOP was removed from GABAergic forebrain neurons of male mice. This male-specific exacerbated sensitivity to heat was restricted to the neuropathic condition and absent in sham mice, concurring with unaltered nociception of naïve DLX5/6-MOP mice in previous assays (Charbogne et al, 2017). The involvement of forebrain areas in the regulation of thermal sensitivity by opioids has been previously described in different models using male mice and rats ( protective mechanism and could be more vulnerable to this aspect of neuropathic pain sensitization.…”

“…forebrain revealed important functions of MOP on reward and motivation (Charbogne et al, 2017), both events that can be altered during sustained pain. On the other hand, DOP from Nav1.8 sensory neurons exert antinociceptive effects in preclinical models of inflammatory and neuropathic pain (Gaveriaux-Ruff et al, 2011), whereas DOP from DLX5/6+ GABAergic forebrain neurons have shown anxiogenic functions that are in contrast with the known overall anxiolytic role of the receptor (Chu Sin Chung et al, 2015).…”

“…Interestingly, MOP of sensory neurons expressing transient receptor potential cation channel subfamily V member 1 (TRPV1; TRPV1+) have also been related to the development of opioid tolerance and hyperalgesia, whereas morphine‐induced spinal cord microgliosis, an event associated with opioid‐induced pain sensitization, was recently found to be independent of MOP activation (Corder et al, ). MOP elimination from DLX5/6+ GABAergic neurons of the forebrain revealed important functions of MOP on reward and motivation (Charbogne et al, ), both events that can be altered during sustained pain. On the other hand, DOP from Nav1.8 sensory neurons exert antinociceptive effects in preclinical models of inflammatory and neuropathic pain (Gaveriaux‐Ruff et al, ), whereas DOP from DLX5/6+ GABAergic forebrain neurons have shown anxiogenic functions that are in contrast with the known overall anxiolytic role of the receptor (Chu Sin Chung et al, ).…”

Loss of mu and delta opioid receptors on neurons expressing dopamine receptor D1 has no effect on reward sensitivity

“…6H). The results showed no appreciable effects of receptor knockdown on morphine reward, which is consistent with previously reported normal CPP in animals with selective deletion of the mu receptor in forebrain GABAergic neurons (Charbogne et al, 2017).…”

“…The complete loss of mu opioid receptors abolishes the rewarding effects of morphine in mice (Matthes et al, 1996), and the reintroduction of mu receptor expression to direct pathway medium spiny neurons of the striatum is sufficient to restore morphine-conditioned place preference (Cui et al, 2014). It has also been reported that the selective deletion of mu opioid receptors in forebrain GABAergic neurons (including those in the striatum) spares opioid-conditioned place preference but affects motivation to self-administer heroin or obtain palatable food (Charbogne et al, 2017). To add further complexity, it appears that opioid signaling in the forebrain may play different roles depending on the type of reward, as the same mutation completely abolishes alcohol-conditioned place preference (Hamida et al, 2019).…”