SIP30 Is Required for Neuropathic Pain-Evoked Aversion in Rats

Abstract

SIP30 (SNAP25 interacting protein of 30) is a SNAP25 interaction protein of 30 kDa that functions in neurotransmitter release. Using a chronic constriction injury (CCI) model of neuropathic pain, we profiled gene expression in the rat spinal cord and brain and identified sip30, which was upregulated after CCI. Here, we show that CCI induced a bilateral increase of SIP30 in the rostral anterior cingulate cortex (rACC), a key brain region that has been implicated in pain affect. We put rats in a chamber with one half painted white (light area) and the other half painted black (dark area), and measured neuropathic pain-evoked place escape/avoidance paradigm (PEAP) to quantify the level of negative emotion evoked by painful stimuli using a Von Frey hair. Inhibition of CCI-mediated induction of SIP30 by intra-rACC injection of shRNA targeting the rat sip30 gene reduced PEAP. Interestingly, knockdown of SIP30 did not affect CCI-induced evoked pain such as heat hyperalgesia and mechanical allodynia. Neither did it affect general learning and memory. CCI-induced upregulation of SIP30 was correlated with activation of ERK, PKA, and CREB in the rACC. Intra-rACC administration of PKA or ERK inhibitors suppressed CCI-induced SIP30 upregulation and blocked the induction of PEAP. Additionally, knockdown of SIP30 suppressed the frequency of mEPSCs and increased paired-pulse ratios in rACC slices and decreased extracellular glutamate concentrations. Together, our results highlight SIP30 as a target of PKA and ERK in the rACC to mediate neuropathic pain-evoked negative emotion via modulation of glutamate release and excitatory synaptic transmission.

Epigenetic upregulation of Cdk5 in the dorsal horn contributes to neuropathic pain in rats

“…Significantly increased CREB activity was observed in the dorsal horn, which may facilitate the expression of BDNF and cyclooxygenase-2 in the dorsal horn in various rodent models of chronic pain [22][23][24]. Increased CREB activity was also observed in the supraspinal brain regions, and contributed to the negative affective components in the rats with CCI [25]. Inhibition of CREB activity significantly alleviated the painful behaviors responsive to thermal and/or mechanical stimuli in the rodent models of chronic pain [22,23].…”

Protein Kinase C Lambda Mediates Acid-Sensing Ion Channel 1a-Dependent Cortical Synaptic Plasticity and Pain Hypersensitivity

“…Place escape/avoidance paradigm (PEAP). PEAP testing was conducted as described previously (LaBuda and Fuchs, 2000;LaGraize et al, 2004;Han et al, 2014). Individual mice were placed in a 50 ϫ 30 ϫ 30 cm chamber on top of a raised mesh floor with one-half painted white (light area) and the other half painted black (dark area).…”

“…Saline-injected and sham-ligated animals were mechanically stimulated in an identical manner as the experimental group. The percentage of time spent on the nonpreferred light side was used to quantify the level of pain affect according to previous methods (LaBuda and Fuchs, 2000;Han et al, 2014).…”

Genomic inbreeding trends in the global Thoroughbred horse population driven by influential sire lines and selection for exercise trait-related genes

“…ZWINT (also known as SIP30) is abundantly expressed in the brain, modulates neurotransmitter release and functions in the mediation of peripheral nerve injury-induced neuropathic pain [28–30]. In rodents ZWINT influences pain-evoked emotional responses [60] and since human athletes have been reported to have a greater ability to tolerate pain than normally active controls [61], it is intriguing to speculate that ZWINT may be involved in the equine response to exercise-induced pain. There were particularly long ROH in this region; 31 of the 305 stallions had ROH >16 Mb between ECA1: 37.8-76.3 Mb (S1 Table); the longest ROH spanned almost 40Mb.…”