Anatomical study of pain that we pursued

Abstract

   In 1990s, to classify dorsal root ganglion (DRG) neurons we examined the distribution and colocalization of mRNAs for neurotrophins and their receptors, neuropeptides (substance P, CGRP, somatostatin) using immunocytochemistry and in situ hybridization histochemistry. In 2000s, we also investi­gated the roles of histamine and serotonin (5–HT) in the pain transmission system. Histamine H1–receptors (H1–Rs) are expressed in non–peptidergic small DRG neurons (15~20％ of DRG neurons) of guinea pig, which may be involved in the transmission of histamine–induced itch. A marked increase in H1–R mRNA levels was observed in peptidergic small DRG neurons after a crush injury of the sciatic nerve. H1–Rs up–regulated in injured afferents may be involved in the potentiation of neuropathic pain. 5–HT2A and 5–HT3 receptors expressed in DRG neurons were also shown to be pro–nociceptive. The role of central 5–HT3 receptors on neural activiti­es recorded from superficial laminae of trigeminal subnucleus caudalis was investigated in rats with or without temporo–mandibular joint inflammation to demonstrate that they mediate pro–nociceptive effects during persistent inflammatory pain.
   At the same time, we started to investigate the role to oncostatin M (OSM), a member of the interleukin–6 family of cytokines, in the development of the pain transmission system. We found receptors for OSM (OSMRbeta) in TRPV1– ⁄ P2X3–double positive small sized DRG neurons. OSM–deficient mice displayed significantly reduced noxious responses in models of acute thermal, mechanical, chemical, and visceral pain, indicating that OSM plays an essential role in the development of a subtype of nociceptive neurons in the DRG. Interleukin–31 receptor A (IL–31RA) is a newly identified type I cytokine receptor, which belongs to gp130 family. Double immunofluorescence staining revealed that IL–31RA is colocalized with OSMRbeta. The developmental expression pattern of IL–31RA was different from that of OSMRbeta, indicating the differential roles of these cytokines in the development and functions of primary afferent system.
   Descending pain control system has long been considered to exert descend­ing inhibition, but recent studies revealed that it also causes facilitation in certain pathological conditions. Chronic restraint stress induced thermal hyperalgesia in rats, in which phosphorylated ERK and levels of tryptophan hydroxylase, a key enzyme of 5–HT production, were increased in the rostral ventromedical medulla (RVM). 5–HT released from the bulbospin­al RVM neurons may exert facilitatory effects on spinal nociceptive processing probably through 5–HT3 receptors. Patients suffering chronic pain originating from deep tissues, such as temporo–mandibular disorder, fibromyalgia, or low back pain, often complain of pain and tenderness in various parts of the body. Systemic enhancement of pain and hyperalgesia induced by regional inflammation or tissue injury may have been caused by the central sensitization and descending facilitation.