Cellular and circuit diversity determines the impact of endogenous opioids in the descending pain modulatory pathway

Abstract

The descending pain modulatory pathway exerts important bidirectional control of nociceptive inputs to dampen and/or facilitate the perception of pain. The ventrolateral periaqueductal gray (vlPAG) integrates inputs from many regions associated with the processing of nociceptive, cognitive, and affective components of pain perception, and is a key brain area for opioid action. Opioid receptors are expressed on a subset of vlPAG neurons, as well as on both GABAergic and glutamatergic presynaptic terminals that impinge on vlPAG neurons. Microinjection of opioids into the vlPAG produces analgesia and microinjection of the opioid receptor antagonist naloxone blocks stimulation-mediated analgesia, highlighting the role of endogenous opioid release within this region in the modulation of nociception. Endogenous opioid effects within the vlPAG are complex and likely dependent on specific neuronal circuits activated by acute and chronic pain stimuli. This review is focused on the cellular heterogeneity within vlPAG circuits and highlights gaps in our understanding of endogenous opioid regulation of the descending pain modulatory circuits.

Adolescent morphine exposure changes the endogenous vlPAG opioid response to inflammatory pain in rats

“…Thereby, vlPAG can modulate pain-related behaviors through its interaction with monoaminergic pathways (Mills et al, 2021). Additionally, the vlPAG is abundant in muopioid receptors, and evidence confirms its key role in opioid-mediated analgesia (McPherson & Ingram, 2022). This shows that exposure to morphine during adolescence reduces the analgesic response to the morphine effect, possibly due to hyperalgesia in response to morphine treatment during adolescence or the reduced efficacy of morphine itself.…”

“…Thereby, vlPAG can modulate pain‐related behaviors through its interaction with monoaminergic pathways (Mills et al., 2021). Additionally, the vlPAG is abundant in mu‐opioid receptors, and evidence confirms its key role in opioid‐mediated analgesia (McPherson & Ingram, 2022).…”

“…vlPAG is a major component of the descending pain modulatory system. It receives inputs from higherorder brain regions, including cortical and subcortical regions, that are involved in processing different aspects of nociception and shaping pain perception (Bandler et al, 1991;McPherson & Ingram, 2022).…”

“…vlPAG is a major component of the descending pain modulatory system. It receives inputs from higher‐order brain regions, including cortical and subcortical regions, that are involved in processing different aspects of nociception and shaping pain perception (Bandler et al., 1991; McPherson & Ingram, 2022). vlPAG sends dense projections to the rostroventral medulla, which is another component of the descending pain modulatory system (Behbehani & Fields, 1979), and sparse efferents to the dorsal horn of the spinal cord (Basbaum & Fields, 1979).…”

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

“…4F and G , and Fig. S6M ), which represents a crucial component of the descending pain modulatory pathway and receives GABAergic input from the CEA [ 2 , 40–44 ]. We examined the effect of optogenetic suppression of the axonal terminals of subtype-1 CEA MOR neurons in the PAG (Fig.…”