| Somatostatin (SOM) is a regulatory peptide produced by hypothalamus. This peptide is widely distributed in both central and peripheral nervous system. Acting as neurotransmitters and neuromodulator, it plays a role in pain modulation. In our previous work, we found that SOM potentially inhabits pain induced by peripheral nerve injury. However, SOM was degregated in a short time, the biological actions of SOM are mediated by its G protein-coupled receptors, and a large number of stable peptide and nonpeptide SOM analogs have been developed to used for our research. SST2A, Somatostatin receptor-2A, a widely distributed and highly affinity for Somatostatin subtype receptor, has been shown to possess anti-tumor. However, the inhibitory functional role of SOM on neuropathic pain has not been elucidated. Based on the previous results, SST2A receptors may be related to the analgesic effect of SOM. In this paper, the mechanism and evidence for SOM inhibits neuronpathic pain through activation of SST2A was studied through animal model, expression and regulation analysis of SST2A in peripheral nervous system, the differences of animal behavior after giving agonist and antagonist specific for SST2A, the differential expression of some important molecules and kinase in signal transduction pathway and so on.At first, after spared nerve injury (SNI), mice developed mechanical allodynia-like behavior as shown by the decrease in withdrawal threshold of the hind paw ipsilateral to the nerve injury as well as the results of cold allodynia and Pin-prick hyperalgesia. This was seen7days after the surgery, with a pronounced effect in14days.This painful behavior has lasted6weeks after nerve injury.Based on this SNI model, we detected the expression of SST2A protein in mouse DRG and spinal cord neurons by immunohistochemistry (IHC) and western blot, In normal control DRGs almost all (>98%) of SST2A-IR expressed calcitonin gene-related peptide (CGRP), a neuronal marker mostly present in peptidergic neurons. After nerve injury, SST2A protein is down-regulated both in SST2A-IR Neuron profiles (NPs) and abundance compared with contralateral side. Even more, the SST2A-IR were colocalized with nNOS、galanin and Y1R; however, No SST2A-IR cell bodies could be detected that colocalized with its ligand SOM in spinal cord and DRGs.We also detected the expression of SST2A mRNA in mouse DRG and spinal cord neurons by In situ hybridization (ISH). This was consistent with the results of IHC.The effect of SOM inhibition on neuropathic pain through SST2A was investigated through pharmacology test. When given Octreotide (SST2A agonist;40μg/kg, i.p.) not CYN154806(SST2A antagonist;6mg/kg, i.p.) significantly increased withdrawal threshold in ipsilateral hind paw, as monitored by mechanical stimulation with Von Frey hairs.Cold allodynia and Pin-prick hyperalgesia were examined after Von Frey test. The withdrawal response duration after cold stimulation or nociceptive mechanical stimulation were significantly reduced in Octreotide-treated animals when compared with saline-treated groups as well as CYN154806-treated groups.Moreover, we detected the effectors of SST2A signal transduction pathway in different drug treatments by IHC. we found that the expression of the phosphorylated-p38MAPK (p-p38) was showed significantly difference in agonist, antagonist and saline treatment mice DRGs. Thus, all of these data provided firstly the concrete evidence for the potential way to treat neuropathic pain by SOM through SST2A-p38MAPK pathway. |
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