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Abstract
Background and Aims In the mammalian brain, the ventrolateral periaqueductal gray (vlPAG) and its neighboring dorsal raphe (DR) nucleus regulate analgesia and anxiety. The vlPAG GABA+ and DR GABA+ neurons display opposite roles in feeding, the specific function of these GABA+ neurons in pain regulation remains unknown. Opioids act on the opioid receptors expressed on vlPAG GABA+ neurons to inhibit GABA release, which in turn exerts anti-nociceptive effects. Although the analgesic potency of morphine indicates the distinct functions of the vlPAG and DR in pain modulation, the involvement of DR GABA+ neurons in opioid anti-nociception is still obscure. We aim to 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.
Methods We combined cell-type specific chemogenetic and optogenetic approaches to dissect the function of GABA+ neurons within the vlPAG and DR in pain processing and emotional responses.
Results The co-activation of vlPAG-DR GABA+ neurons induced hypersensitivity to mechanical stimulation and anxiety-like behavior, while the inhibition of vlPAG-DR GABA+ neurons led to anti-nociception and anti-anxiety effects on mice with inflammatory pain. Moreover, we found the opposite effects of separately manipulating vlPAG GABA+ and DR GABA+ neurons on the nociceptive responses.
Co-activation of vlPAG and DR GABAergic (vlPAG-DRGABA+) neurons promotes mechanical sensitivity and anxiety
The vlPAG GABA+ and DR GABA+ neurons display opposite roles in pain regulation
Inhibition of vlPAG-DR GABA+ or activation of DR GABA+ neurons attenuates mechanical hypersensitivity in inflammatory pain
Conclusions The activation and inhibition of vlPAG-DR GABA+ neurons bidirectionally regulate nociception and anxiety-like behaviors. We also found that vlPAG GABA+ and DR GABA+ neurons play different roles in modulating the sensitivity to mechanical stimuli in both naïve and inflammatory pain mice.