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

Int J Mol Sci. 2020 Oct 21;21(20):7788. doi: 10.3390/ijms21207788.


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 (SST4) without endocrine actions. SST4 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 SST4 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 SST4-expressing neurons. Intense or moderate SST4 expression was demonstrated predominantly in glutamatergic neurons in the major components of the pain matrix mostly also involved in mood regulation. The SST4 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 SST4 agonists as novel analgesic and antidepressant candidates.

Keywords: M-current; RNA scope in situ hybridization; SST4 receptor; mood regulation; pain; somatosensory cortex; β-galactosidase immunohistochemistry.

MeSH terms

  • Affect / physiology
  • Analgesics / pharmacology*
  • Animals
  • Brain / cytology
  • Brain / metabolism*
  • Butanes / pharmacology
  • CHO Cells
  • Cricetulus
  • Electrophysiology / methods
  • Humans
  • Male
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Molecular Targeted Therapy
  • Naphthalenes / pharmacology
  • Neurons / drug effects
  • Neurons / metabolism*
  • Receptors, Somatostatin / agonists
  • Receptors, Somatostatin / genetics*
  • Receptors, Somatostatin / metabolism*
  • Sulfones / pharmacology
  • Vesicular Glutamate Transport Protein 1 / genetics


  • Analgesics
  • Butanes
  • Naphthalenes
  • Receptors, Somatostatin
  • SLC17A7 protein, human
  • Sulfones
  • Vesicular Glutamate Transport Protein 1
  • somatostatin receptor subtype-4
  • (1'S, 2S)-4-amino-N-(1'-carbamoyl-2'-phenylethyl)-2-(4''-methyl-1''-naphthalenesulfonylamino)butanamide