The Contributions of Mu-Opioid Receptors on Glutamatergic and GABAergic Neurons to Analgesia Induced by Various Stress Intensities

Abstract

The endogenous opioid system plays a crucial role in stress-induced analgesia. Mu-opioid receptors (MORs), one of the major opioid receptors, are expressed widely in subpopulations of cells throughout the CNS. However, the potential roles of MORs expressed in glutamatergic (MOR Glut ) and γ-aminobutyric acidergic (MOR GABA ) neurons in stress-induced analgesia remain unclear. By examining tail-flick latencies to noxious radiant heat of male mice, here we investigated the contributions of MOR GABA and MOR Glut to behavioral analgesia and activities of neurons projecting from periaqueductal gray (PAG) to rostral ventromedial medulla (RVM) induced by a range of time courses of forced swim exposure. The moderate but not transitory or prolonged swim exposure induced a MOR-dependent analgesia, although all of these three stresses enhanced β-endorphin release. Selective deletion of MOR GABA but not MOR Glut clearly attenuated analgesia and blocked the enhancement of activities of PAG-RVM neurons induced by moderate swim exposure. Under transitory swim exposure, in contrast, selective deletion of MOR Glut elicited an analgesia behavior via strengthening the activities of PAG-RVM neurons. These results indicate that MOR-dependent endogenous opioid signaling participates in nociceptive modulation in a wide range, not limited to moderate, of stress intensities. Endogenous activation of MOR GABA exerts analgesia, whereas MOR Glut produces antianalgesia. More importantly, with an increase of stress intensities, the efficiencies of MORs on nociception shifts from balance between MOR Glut and MOR GABA to biasing toward MOR GABA -mediated processes. Our results point to the cellular dynamic characteristics of MORs expressed in excitatory and inhibitory neurons in pain modulation under various stress intensities.

Single-neuron projectome-guided analysis reveals the neural circuit mechanism underlying endogenous opioid antinociception

“…S4V–Y ). These CEA neurons are known to be GABAergic [ 6 ]; thus, this result is consistent with previous studies showing that MORs in GABAergic neurons are involved in endogenous opioid analgesia [ 6 , 7 ]. In contrast, we found that the ablation of MOR-expressing neurons in the ACB, which is enriched with GABAergic neurons, did not affect CFA-induced persistent hyperalgesia (Fig.…”

“…An important issue of MOR involvement in endogenous opioid antinociception is whether MORs in the CEA are activated by locally released opioids. Enhanced release of opioids in the brain has been observed in several situations, such as stress-induced analgesia, and the effects could be blocked by naloxone [ 3 , 5 , 7 ]. Consistently, our pharmacological experiments showed that bilateral CEA infusion of naloxone, a competitive opioid antagonist in wild-type mice, blocked endogenous opioid antinociception, indicating the requirement of opioid receptor activation by endogenous opioid peptides during CFA-induced persistent hyperalgesia.…”

“…Recent studies have begun to explore how MOR activation leads to endogenous opioid analgesia. Genetic deletion experiments in mice showed that MOR activation in supraspinal GABAergic neurons is required [ 6 , 7 ]. However, the site of action of endogenous opioids remains unclear.…”

Fentanyl-Induced Respiratory Depression and Locomotor Hyperactivity Are Mediated by μ-Opioid Receptors Expressed in Somatostatin-Negative Neurons

“…It is plausible that the lack of MORs may affect the behavioral and respiratory responses to the stress associated with intraperitoneal injection. In fact, endogenous MOR circuits are involved in stress (Du et al, 2022), and the absence of MORs may affect the stress response following injection. Overall, our results showed that respiratory rate depression by fentanyl was mediated by MORs in freely behaving mice.…”

μ-opioid receptor agonists and psychedelics: pharmacological opportunities and challenges

“…The MOR localizes in γ-aminobutyric acid ( GABA ) interneurons in the neocortex and is proposed to disinhibit glutamate-driven outflow to its terminal fields ( Taki et al, 2000 ; Ferezou et al, 2007 ). A subset of cortical glutamate neurons is also reported to express MOR ( Birdsong et al, 2019 ; Zhang et al, 2020 ; Du et al, 2022 ). Opportunistically, the 5-HT 2A R localizes within these key regions ( Figure 1 ) ( Liu et al, 2014 ; Howell and Cunningham, 2015 ; Browne et al, 2019 ; Cunningham et al, 2020 ; Nagai et al, 2020 ).…”