SGK1.1 isoform is involved in nociceptive modulation, offering a protective effect against noxious cold stimulus in a sexually dimorphic manner

Abstract

The serum and glucocorticoid-regulated kinase 1 (SGK1) is a widely expressed protein in the Central Nervous System (CNS), involved in regulating the activity of a wide variety of ion channels and transporters and physiological functions, such as neuronal excitability. SGK1.1 is a neuronal splice isoform of SGK1, expressed exclusively in the CNS, distributed in brain and cerebellum, that decreases neuronal excitability via up-regulation of M-current, linked to Kv7.2/3 potassium channels. Strategies to maintain increased SGK1.1 activity could be helpful in decreasing neuronal hyperexcitability, as occurs in neuropathic pain. Transgenic mice overexpressing SGK1.1 (B6.Tg.sgk1) offer a particularly relevant opportunity to assess the physiological involvement of this protein in nociception. Behavior and physiological nociception were evaluated in male and female B6.Tg.sgk1 and wild-type mice (B6.WT), characterizing nociceptive thresholds to different nociceptive stimuli (thermal, chemical and mechanical), as well as the electrophysiological properties of cutaneous sensory Aδ-fibres isolated from the saphenous nerve. The acute antinociceptive effect of morphine was also evaluated. Compared with B6.WT animals, male and female B6.Tg.sgk1 mice showed increased spontaneous locomotor activity. Regarding nociception, there were no differences between transgenic and wild-type mice in heat, chemical and mechanical thresholds, but interestingly, male B6.Tg.sgk1 mice were less sensitive to cold stimulus; B6.Tg.sgk1 animals showed lower sensitivity to morphine. Electrophysiological properties of cutaneous primary afferent fibres were maintained. This is the first demonstration that the SGK1.1 isoform is involved in nociceptive modulation, offering a protective effect against noxious cold stimulus in a sexually dimorphic manner. B6.Tg.sgk1 mice offer a particularly relevant opportunity to further analyze the involvement of this protein in nociception, and studies in models of chronic, neuropathic pain are warranted.

Keywords: M-current; Nociception; SGK1 protein; SGK1.1; Transgenic mice.