Reduced Capsaicin-Induced Mechanical Allodynia and Neuronal Responses in the DRG in the Presence of Shp1 Overexpression

Vroman, R.; Ishihara, S.; Fullam, S.; Wood, M. J.; Adamczyk, N. S.; Lomeli, N.; Malfait, F.; Malfait, A.-M.; Miller, R. E.; Markovics, A.

doi:10.1101/2024.01.23.576758

bioRxiv · 10.1101/2024.01.23.576758

Reduced Capsaicin-Induced Mechanical Allodynia and Neuronal Responses in the DRG in the Presence of Shp1 Overexpression

Vroman, R.·Ishihara, S.·Fullam, S.·Wood, M. J.·Adamczyk, N. S.·Lomeli, N.·Malfait, F.·Malfait, A.-M.·Miller, R. E.·Markovics, A.

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Abstract

Transient Receptor Potential Vanilloid 1 (TRPV1) is a nonselective cation channel expressed by pain-sensing neurons and has been an attractive target for the development of drugs to treat pain. Recently, Src homology region 2 domain-containing phosphatase-1 (SHP-1) was shown to dephosphorylate TRPV1 in dorsal root ganglia (DRG) neurons, which was linked with alleviating different pain phenotypes. These previous studies were performed in male rodents only and did not directly investigate the role of SHP-1 in TRPV-1 mediated sensitization. Therefore, our goal was to determine the impact of Shp1 overexpression on TRPV1-mediated neuronal responses and capsaicin-induced pain behavior in mice of both sexes. Twelve-week-old male and female mice overexpressing Shp1 (Shp1-Tg) and their wild type (WT) littermates were used. Shp1 overexpression was confirmed in the DRG of Shp1-Tg mice by RNA in situ hybridization and RT-qPCR. Trpv1 and Shp1 were found to be co-expressed in DRG sensory neurons in both genotypes. Functionally, this overexpression resulted in lower magnitude intracellular calcium responses to 200 nM capsaicin stimulation in DRG cultures from Shp1-Tg mice compared to WTs. In vivo, we tested the effects of Shp1 overexpression on capsaicin-induced pain through a model of capsaicin footpad injection. While capsaicin injection evoked nocifensive behavior (paw licking) and paw swelling in both genotypes and sexes, only WT mice developed mechanical allodynia after capsaicin injection. We observed similar level of TRPV1 protein expression in the DRG of both genotypes, however, a higher amount of tyrosine phosphorylated TRPV1 was detected in WT DRG. These experiments suggest that, while SHP-1 does not mediate the acute swelling and nocifensive behavior induced by capsaicin, it does mediate a protective effect against capsaicin-induced mechanical allodynia in both sexes. The protective effect of SHP-1 might be mediated by TRPV1 dephosphorylation in capsaicin-sensitive sensory neurons of the DRG.

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Vroman, R., Ishihara, S., Fullam, S., Wood, M. J., Adamczyk, N. S., Lomeli, N., Malfait, F., Malfait, A.-M., Miller, R. E., Markovics, A.. 2024-01-24. Reduced Capsaicin-Induced Mechanical Allodynia and Neuronal Responses in the DRG in the Presence of Shp1 Overexpression. https://doi.org/10.1101/2024.01.23.576758

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