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This paper is dedicated to the memory of János Szolcsányi (1938–2018), an outstanding Hungarian scientist. Among analgesics that act on pain receptors, he identified capsaicin as a selective lead molecule. He studied the application of capsaicin and revealed several physiological (pain, thermoregulation) and pathophysiological (inflammation, gastric ulcer) mechanisms. He discovered a new neuroregulatory system without sensory efferent reflex and investigated its pharmacology. The authors of this review are his former Ph.D. students who carried out their doctoral work in Szolcsányi's laboratory between 1985 and 2010 and report on the scientific results obtained under his guidance. His research group provided evidence for the triple function of the peptidergic capsaicin-sensitive sensory neurons including classical afferent function, local efferent responses, and remote, hormone-like anti-inflammatory, and antinociceptive actions. They also proposed somatostatin receptor type 4 as a promising drug target for the treatment of pain and inflammation. They revealed that neonatal capsaicin treatment caused no acute neuronal death but instead long-lasting selective ultrastructural and functional changes in B-type sensory neurons, similar to adult treatment. They described that lipid raft disruption diminished the agonist-induced channel opening of the TRPV1, TRPA1, and TRPM8 receptors in native sensory neurons. Szolcsányi's group has developed new devices for noxious heat threshold measurement: an increasing temperature hot plate and water bath. This novel approach proved suitable for assessing the thermal antinociceptive effects of analgesics as well as for analyzing peripheral mechanisms of thermonociception. [ABSTRACT FROM AUTHOR]

Somatostatin receptor subtype 4 (SST4) has been shown to mediate analgesic, antidepressant and anti-inflammatory functions without endocrine actions; therefore, it is proposed to be a novel target for drug development. To overcome the species differences of SST4 receptor expression and function between humans and mice, we generated an SST4 humanized mouse line to serve as a translational animal model for preclinical research. A transposon vector containing the hSSTR4 and reporter gene construct driven by the hSSTR4 regulatory elements were created. The vector was randomly inserted in Sstr4-deficient mice. hSSTR4 expression was detected by bioluminescent in vivo imaging of the luciferase reporter predominantly in the brain. RT-qPCR confirmed the expression of the human gene in the brain and various peripheral tissues consistent with the in vivo imaging. RNAscope in situ hybridization revealed the presence of hSSTR4 transcripts in glutamatergic excitatory neurons in the CA1 and CA2 regions of the hippocampus; in the GABAergic interneurons in the granular layer of the olfactory bulb and in both types of neurons in the primary somatosensory cortex, piriform cortex, prelimbic cortex and amygdala. This novel SST4 humanized mouse line might enable us to investigate the differences of human and mouse SST4 receptor expression and function and assess the effects of SST4 receptor agonist drug candidates. [ABSTRACT FROM AUTHOR]

Background: Somatostatin released from the capsaicin-sensitive sensory nerves mediates analgesic and anti-inflammatory effects via its receptor subtype 4 (SST4) without influencing endocrine functions. Therefore, SST4 is considered to be a novel target for drug development in pain, especially chronic neuropathy which is a great unmet medical need. Purpose and Experimental Approach: Here, we examined the in silico binding, SST4-linked G protein activation and β-arrestin activation on stable SST4 expressing cells and the effects of our novel pyrrolo-pyrimidine molecules (20, 100, 500, 1,000, 2,000 µg·kg−1) on partial sciatic nerve ligation-induced traumatic mononeuropathic pain model in mice. Key Results: The novel compounds bind to the high affinity binding site of SST4 the receptor and activate the G protein. However, unlike the reference SST4 agonists NNC 26-9100 and J-2156, they do not induce β-arrestin activation responsible for receptor desensitization and internalization upon chronic use. They exert 65–80% maximal anti-hyperalgesic effects in the neuropathy model 1 h after a single oral administration of 100–500 µg·kg−1 doses. Conclusion and Implications: The novel orally active compounds show potent and effective SST4 receptor agonism in vitro and in vivo. All four novel ligands proved to be full agonists based on G protein activation, but failed to recruit β-arrestin. Based on their potent antinociceptive effect in the neuropathic pain model following a single oral administration, they are promising candidates for drug development. [ABSTRACT FROM AUTHOR]

Background: Somatostatin released from the capsaicin-sensitive sensory nerves mediates analgesic and anti-inflammatory effects via its receptor subtype 4 (SST 4 ) without influencing endocrine functions. Therefore, SST 4 is considered to be a novel target for drug development in pain, especially chronic neuropathy which is a great unmet medical need. Purpose and Experimental Approach: Here, we examined the in silico binding, SST 4 -linked G protein activation and β-arrestin activation on stable SST 4 expressing cells and the effects of our novel pyrrolo-pyrimidine molecules (20, 100, 500, 1,000, 2,000 µg·kg -1 ) on partial sciatic nerve ligation-induced traumatic mononeuropathic pain model in mice. Key Results: The novel compounds bind to the high affinity binding site of SST 4 the receptor and activate the G protein. However, unlike the reference SST 4 agonists NNC 26-9100 and J-2156, they do not induce β-arrestin activation responsible for receptor desensitization and internalization upon chronic use. They exert 65-80% maximal anti-hyperalgesic effects in the neuropathy model 1 h after a single oral administration of 100-500 µg·kg -1 doses. Conclusion and Implications: The novel orally active compounds show potent and effective SST 4 receptor agonism in vitro and in vivo . All four novel ligands proved to be full agonists based on G protein activation, but failed to recruit β-arrestin. Based on their potent antinociceptive effect in the neuropathic pain model following a single oral administration, they are promising candidates for drug development., Competing Interests: ZH is the strategic director and shareholder of PharmInVivo Ltd. (Pécs, Hungary) and shareholder of Algonist Biotechnologies Gmbh, (Wien, Austria). EP is the scientific director and shareholder of PharmInVivo Ltd. (Pécs, Hungary) and shareholder of Algonist Biotechnologies Gmbh, (Wien, Austria). ES is also a shareholder of Algonist Biotechnologies Gmbh, (Wien, Austria). PB is the head of R&D at Avicor Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kántás, Szőke, Börzsei, Bánhegyi, Asghar, Hudhud, Steib, Hunyady, Horváth, Kecskés, Borbély, Hetényi, Pethő, Pintér and Helyes.)