Characterization of Neurons Expressing the Novel Analgesic Drug Target Somatostatin Receptor 4 in Mouse and Human Brains.

Somatostatin is an important mood and pain-regulating neuropeptide, which exerts analgesic, anti-inflammatory, and antidepressant effects via its Gi protein-coupled receptor subtype 4 without endocrine actions. is suggested to be a unique novel drug target for chronic neuropathic pain, and depression, as a common comorbidity. However, its neuronal expression and cellular mechanism are poorly understood. Therefore, our goals were (i) to elucidate the expression pattern of mRNA, (ii) to characterize neurochemically, and (iii) electrophysiologically the neuronal populations in the mouse and human brains. Here, we describe duanyu1942₄ expression pattern in the nuclei of the mouse nociceptive and anti-nociceptive pathways as well as in human brain regions, and provide neurochemical and electrophysiological characterization of the neurons. Intense or moderate duanyu1942₄ expression was demonstrated predominantly in glutamatergic neurons in the major components of the pain matrix mostly also involved in mood regulation. The duanyu1942₄ agonist J-2156 significantly decreased the firing rate of layer V pyramidal neurons by augmenting the depolarization-activated, non-inactivating K⁺ current (M-current) leading to remarkable inhibition. These are the first translational results explaining the mechanisms of action of duanyu1942₄ agonists as novel analgesic and antidepressant candidates.

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