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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 (SST 4 ) without endocrine actions. SST 4 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 Sstr4 / SSTR4 mRNA, (ii) to characterize neurochemically, and (iii) electrophysiologically the Sstr4 / SSTR4 -expressing neuronal populations in the mouse and human brains. Here, we describe SST 4 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 SST 4 -expressing neurons. Intense or moderate SST 4 expression was demonstrated predominantly in glutamatergic neurons in the major components of the pain matrix mostly also involved in mood regulation. The SST 4 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 SST 4 agonists as novel analgesic and antidepressant candidates.

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