Upregulation of Spinal ASIC1 and NKCC1 Expression Contributes to Chronic Visceral Pain in Rats

Abstract

Aims: To determine whether acid-sensing ion channel 1 (ASIC1)–sodium-potassium-chloride cotransporter 1 (NKCC1) signaling pathway participates in chronic visceral pain of adult rats with neonatal maternal deprivation (NMD).Methods: Chronic visceral pain was detected by colorectal distension (CRD). Western blotting and Immunofluorescence were performed to detect the expression and location of ASIC1 and NKCC1. Whole-cell patch-clamp recordings were performed to record spinal synaptic transmission.Results: The excitatory synaptic transmission was enhanced and the inhibitory synaptic transmission was weakened in the spinal dorsal horn of NMD rats. ASIC1 and NKCC1 protein expression in the spinal dorsal horn was significantly up-regulated in NMD rats. Incubation of Amiloride reduced the amplitude of mEPSCs. Incubation of Bumetanide (BMT) increased the amplitude of mIPSCs. Intrathecal injection of ASIC1 or NKCC1 inhibitors reversed the threshold of CRD in NMD rats. Also, Amiloride treatment significantly reversed the expression of NKCC1 in the spinal dorsal horn of NMD rats.Conclusion: Our data suggest that the ASIC1-NKCC1 signaling pathway is involved in chronic visceral pain in NMD rats.

A paraventricular hypothalamic nucleus input to ventral of lateral septal nucleus controls chronic visceral pain

“…Chronic visceral pain was induced by neonatal maternal deprivation (NMD), as previously described. 8 , 27 In brief, from day 2 to day 15 after birth, the newborn C57BL/6 male mouse pups of the NMD group were placed in a separate box with an electric blanket for 3 hours. After the separation period, the pups were placed back in their dams.…”

“… 5 Neonatal maternal deprivation (NMD) is a typical early life stress that has been shown to induce visceral pain behavior. 18 , 27 At present, most research studies on visceral pain have focused on the investigation of the molecular events underlying the peripheral nervous system and the spinal cord. 29 , 41 , 47 However, the studies that have focused on the brain are very limited, and the role of the brain in regulating visceral pain remains largely unclear.…”

Acid-sensing ion channel 1a in the central nucleus of the amygdala regulates anxiety-like behaviors in a mouse model of acute pain

“…The acid-sensing ion channel (ASIC) family consists of six subtypes (ASIC1a, 1b, 2a, 2b, 3, and 4) encoded by four genes ( Hamann et al, 2015 ; Zhu et al, 2022 ). ASIC1a has been frequently studied because of its abundant levels in the mammalian central nervous system ( Wemmie et al, 2003 ; Li et al, 2020 ). In addition, ASIC1a is present in areas of brain regions that are important in the pain process, including the ACC and hippocampus, as well as the amygdala ( Alvarez de la Rosa et al, 2003 ).…”

Spinal VGLUT3 lineage neurons drive visceral mechanical allodynia but not visceromotor reflexes

“…As a result of this circuit-level segregation, a selective loss of cutaneous affective pain may not be detected via assays that only measure first-line reflexive-defensive reactions (Ma, 2022; Mogil, 2020). Meanwhile, despite great clinical relevance and unmet medical need, modern genetic and viral tools have rarely been used to characterize spinal circuits transmitting visceral sensory information, even though electrophysiological, molecular and behavioral studies have revealed sensitization in spinal neurons following visceral inflammation or stress (Defaye et al, 2022; Farrell et al, 2017; Gamboa-Esteves et al, 2004; Harrington et al, 2012; Honore et al, 2002; Lai et al, 2011; Li et al, 2020; Long et al, 2022; Nishida et al, 2022; Traub, 2000; Wang et al, 2005; Wu et al, 2022; Zhang et al, 2013). As such, it is still poorly understood how nociceptive and affective dimensions of visceral sensory information are transmitted through the spinal cord.…”