Divergent modulation of pain and anxiety by GABAergic neurons in the ventrolateral periaqueductal gray and dorsal raphe

Abstract

The ventrolateral periaqueductal gray (vlPAG) collaborates with the dorsal raphe (DR) in pain regulation and emotional response. However, the roles of vlPAG and DR γ-aminobutyric acid (GABA)-ergic neurons in regulating nociception and anxiety are contradictory and poorly understood. Here, we observed that pharmacogenetic co-activation of vlPAG and DR GABAergic (vlPAG-DRGABA+) neurons enhanced sensitivity to mechanical stimulation and promoted anxiety-like behavior in naïve mice. Simultaneous inhibition of vlPAG-DRGABA+ neurons showed adaptive anti-nociception and anti-anxiety effects on mice with inflammatory pain. Notably, vlPAGGABA+ and DRGABA+ neurons exhibited opposing effects on the sensitivity to mechanical stimulation in both naïve state and inflammatory pain. In contrast to the role of vlPAGGABA+ neurons in pain processing, chemogenetic inhibition and chronic ablation of DRGABA+ neurons remarkably promoted nociception while selectively activating DRGABA+ neurons ameliorated inflammatory pain. Additionally, utilizing optogenetic technology, we observed that the pronociceptive effect arising from DRGABA+ neuronal inhibition was reversed by the systemic administration of morphine. Our results collectively provide new insights into the modulation of pain and anxiety by specific midbrain GABAergic subpopulations, which may provide a basis for cell type-targeted or subregion-targeted therapies for pain management.

Pain-related behavioral and electrophysiological actions of dynorphin A (1-17)

“…In light of several recent studies it is clear that there are multiple levels of processing that occur in the vlPAG that relate to opioid signaling and descending modulation of pain. [32][33][34] Our findings from current-clamp recordings demonstrate that the intrathecal dynorphin effect results in an excitability increase in an unbiased sample of vlPAG neurons. The pronociceptive effect of chemogenetic activation of vlPAG GABA 32 neurons may relate to our findings, as we observed the increase in pain behavior along with increased vlPAG excitability.…”

The genetic architecture of pain intensity in a sample of 598,339 U.S. veterans

“…Evidence that GABAergic neurons are cells of specific interest is a key novel finding. GABA has long been implicated in the modulation and perception of pain 99-101 and previous work has implicated specific GABAergic activity in the midbrain as a modulator of pain and anxiety 102 . Altered GABA levels have been reported in individuals with various types of pain 103,104 , and have been associated with greater selfreported pain 105 .…”

Brainstem nuclei responsive to cystometry in both endometriosis and cystitis rat models: C‐fos immunohistochemistry study

“…other brainstem nuclei including DR, Rob, and KF are also proved to be involved in pain modulation. [35][36][37] On the other hand, AP is part of the vagal complex and participates in various cardiovascular functions. 38 So, the involvement of this area could be part of the coordination between the urinary and the cardiovascular functions during ENDO condition.…”