Opioid presynaptic disinhibition of the midbrain periaqueductal grey descending analgesic pathway

Abstract

Background and Purpose: The midbrain periaqueductal grey (PAG) plays a central role in modulating pain through a descending pathway that projects indirectly to the spinal cord via the rostroventral medial medulla (RVM). While opioids are potent analgesics that target the PAG, their cellular actions on descending projection neurons are unclear. Experimental Approach: Patch clamp recordings in voltage-and current-clamp mode were made from acutely prepared PAG slices from animals that received retrograde tracer injections into the RVM. Key Results: The μ-agonist DAMGO reduced GABAergic evoked inhibitory postsynaptic currents (IPSCs) in retro-labelled, RVM-projecting neurons to a greater extent than in unlabelled neurons. The κ-opioid agonist U69593 reduced evoked IPSCs to a similar extent in both neuronal groups, while the δ-opioid agonist deltorphin-II was without effect. DAMGO and U69593 both produced a reduction in the rate, but not amplitude of spontaneous miniature IPSCs and asynchronous evoked IPSCs in retrolabelled neurons. DAMGO and U69593 also suppressed glutamatergic EPSCs in retro-labelled and unlabelled neurons. The DAMGO inhibition of evoked EPSCs, however, was less than that for evoked IPSCs in retro-labelled, but not unlabelled neurons. In current clamp, DAMGO produced a depolarizing increase in evoked postsynaptic potentials in retro-labelled neurons, but directly inhibited unlabelled neurons. Conclusion and Implications: These findings suggest that μ-opioids activate the descending analgesic pathway from the midbrain PAG by a combination of presynaptic disinhibition of RVM-projecting neurons and postsynaptic inhibition of presumptive interneurons.

The Role of Neuropeptide B and Its Receptors in Controlling Appetite, Metabolism, and Energy Homeostasis

“…injection of NPB in rats reduced licking duration in the formalin test, which indicates an analgesic role of the peptide against chemically induced pain [ 11 ]. These effects could be conferred via NPB and NPBWR1, which are found in the periaqueductal gray matter and amygdala, areas that are also known to express opioid receptors [ 39 ]. It is worth mentioning that NPBWR1 binds non-selective opioid ligands such as β-endorphin [ 13 ].…”

Physiologically distinct neurons within the ventrolateral periaqueductal gray are not defined by mu-opioid receptor expression but are differentially activated by persistent inflammation

“…The copyright holder for this preprint this version posted June 17, 2021. ; https://doi.org/10.1101/2021.06.16.448597 doi: bioRxiv preprint used to identify MOR-expressing neurons, have been limited to small numbers of vlPAG neurons (Park et al, 2010;Lau et al, 2020). Thus, a more comprehensive study was necessary to determine if opioid-sensitive neurons represent a single functional subset of neurons in the vlPAG with distinct firing properties.…”

“…Opioids disinhibit vlPAG output neurons to the rostral ventromedial medulla (RVM) to produce analgesia (Basbaum and Fields, 1984; Cheng et al, 1986; Lau et al, 2020). In a subpopulation of opioid-sensitive vlPAG neurons, postsynaptic MORs activate G protein-coupled inwardly-rectifying potassium channels (GIRKs) hyperpolarizing the neurons (Barbaresi and Manfrini, 1988; Chieng and Christie, 1994; Kalyuzhny and Wessendorf, 1998; McPherson et al, 2018), some of which are local GABAergic neurons (Basbaum and Fields, 1978; Barbaresi and Manfrini, 1988; Reichling and Basbaum, 1990; Kalyuzhny and Wessendorf, 1998).…”

“…Although it is tempting to use MOR as a cell-type specific marker, morphological features of opioid-sensitive and -insensitive neurons are similar (Chieng and Christie, 1994) and MORs are expressed on both GABAergic and non-GABA neurons within this region (Zhang et al, 2020). Further, electrophsyiological characteristics that have been used to identify MOR-expressing neurons, have been limited to small numbers of vlPAG neurons (Park et al, 2010; Lau et al, 2020). Thus, a more comprehensive study was necessary to determine if opioid-sensitive neurons represent a single functional subset of neurons in the vlPAG with distinct firing properties.…”

Involvement of the Ventrolateral Periaqueductal Gray Matter-Central Medial Thalamic Nucleus-Basolateral Amygdala Pathway in Neuropathic Pain Regulation of Rats

“…The ventrolateral quadrant of the periaqueductal gray matter (vlPAG) responds specifically to somatic nociceptive stimuli (Sanders et al, 1980 ). Recent studies of the vlPAG have focused on its role in the descending pain pathway (Huang et al, 2019 ; Lau et al, 2020 ). However, vlPAGs ascendingly project to the intralaminar thalamic nuclei in rats, including the CM, parafascicular, paracentral, and central lateral nuclei (Krout and Loewy, 2000 ).…”