ラット神経因性疼痛における末梢セロトニン受容体 (5-HT_<2A>) 活性化の関与 : 熱性痛覚過敏および脊髄細胞傷害による評価

Abstract

The mechanisms of pathological pain processes including hyperalgesia and allodynia after peripheral nerve injury have not been fully understood. Several recent studies have suggested that neuronal plasticity of spinal neuronal transmission such as glutamatergic nerve activation and its related chemical cascades may be responsible for developing pain sensitization. Therefore, it is reasonable to determine whether apoptosis results from gulutamatergic activation via acceleration of intracellular and nuclear signaling processes. Sarpogrelate HCl (MCI) is newly produced compound and that affects on Serotoninergic neurons (5-HT_<2A>). The present study was designed to investigate the response to thermal stimuli in relation to histopathological changes after chronic construction injury (CCI) in rats. In addition, the present study was evaluated whether seroninergic neurons located in peripheral site may regulate neuropathic pain produced by CCI. The left sciatic nerve of SD rat were ligated under pentobarbital anesthesia. Paw withdrawal latency (PWL), response to thermal stimuli, was measured by using the plantar testing apparatus before CCI and at 6, 8, and 10th days after CCI. Immunohistchemical stainig for apoptosis (TUNEL) and early degeneration (H-E) was performed with light microscope at the corresponding days. TUNEL stain score was counted positive neurons and HE stain score was obtained as 0 : normal neuron to 3 : more than 50% neuronal degeneration. In addition, rat was divided into the three series of study by drug administration ; 1) Saline 0.5ml i.p., 2) MCI 10mg/kg i.p. and 3) MCI+α-methyl-5HT 10mg/kg i.p., 5-HT_<2A> agonist. The hyperalgesia evoked at 6 day after sciatic nerve ligation in rats. In these rats, the apoptosis development was found more at 6 than 10 day. In contraction, the neuronal degeneration occurred more at 10 day. By administration of MCI, pain behavier, apoptosis, and neuronal degeneration was inhibited significantly. The present results demonstrate that apoptosis development was firstly found in the superficial layer of spinal cord in early state of hyperalgesia. This may be suggested that sciatic nerve injury leads to increased ascending inputs or glutamatergic nerve activation followed by derangement of intracellular signaling-intranuclear process (c-fos exprerssion) in the spinal cord which causes apoptosis leading to pain behaviour. It is also suggested that the delayed appearance of neuronal degeneration in the laminae III-IV causes dysfunction of inhibitory interneurons located in this regions and this neuronal damaged is sufficient to develop the sustained pain behaviour. In addition, MCI adoministration provokes antinociceptive effect on neuropathic pain produced by CCI and this effect was reversed by 5-HT_<2A> receptor agonist. It is suggested that the serotoninergic activation take a part of neuropathic pain, the inhibition of this activation is very important of treatment of neuropathic pain.