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.

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   We conducted a retrospective study to evaluate postoperative pain intensity and side effects caused by fentanyl administered during patient–controlled epidural analgesia (PCEA) with a mixture of ropivacaine (1.5 mg/ml) and fentanyl (1 µg/ml or 2 µg/ml) in elderly patients who underwent laparoscopic–assisted colon surgery (LAC) for colon cancer.
   A total of 68 elderly patients aged >70 years were divided into 4 groups by gender and fentanyl dose administered during PCEA with 1.5 mg/ml of ropivacane: an LM group, which included 6 males who received fentanyl at a dose of 1 µg/ml during PCEA; an LF group, which included 18 females who received fentanyl at a concentration of 1 µg/ml during PCEA; an HM group, which included 27 males who received fentanyl at a concentration of 2 µg/ml during PCEA; and an HF group, which included 17 females who received fentanyl at a concentration of 2 µg/ml during PCEA. PCEA was admin­istered at the rate of 3 ml/h using the CADD–Legacy^® PCA machine type. The bolus dose was 2 ml, the lock–out period was 15 min, and the maximum effective number of bolus was 2 times/h. Pain intensity at rest and during movement was measured twice daily for 4 days following surgery using a 100–mm nongraduated visual analog scale (VAS). One–way analysis of variance, the Kruskal–Wallis test, and the chi–square test were used for statistical analyses depending on the type of data. A p–value of <0.05 was considered statistically significant. If a significant difference was observed, a multiple comparison test of Bonferroni or Dunn’s post–test was used.
   Pain intensity at rest and during movement was not significantly different among the 4 groups. The number of PCEA bolus injections administered and the number of requests for PCEA were comparable among the 4 groups. The incidence of postoperative itching was 88.2％ in the HF group; this was significantly higher than that in the HM (51.9％) and LF groups (33.3％). The incidence of postoperative nausea and vomiting were 47.1％ in the HF group; this was significantly higher than that in the HM group (11.1％). There was no case of lower limb paralysis after 1 postoperative day in all groups.
   In conclusion, the findings of this study suggest that the degree and frequency of postoperative itching caused by fentanyl administered during PCEA can be potentially decreased, without altering postoperative pain intensity, by lowering the concentration of fentanyl combined with a low dose of ropivacane following LAC in elderly female patients.

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   The present study aimed to examine the common opinion that “acute low back pain subsides early whereas chronic low back pain (LBP) is resistant to treatment”. Pain intensity in 94 LBP patients (mean age 54 years) was measured using a visual analog scale (VAS) and the change in VAS score (∆VAS, mm/day) was investigated. The initial ∆VAS (∆VAS–i) and the entire ∆VAS (∆VAS–t) were investigated. ∆VAS–i was calculated from examina­tions at the first and second patient visits. ∆VAS–t was calculated from examinations at the first and last patient visits. Patients were classified into an acute group, who had less than three months (≤ 3M) duration of their current LBP, and a chronic group, who had more than three months (> 3M) duration of their current LBP. Patients were also classified according to the duration of their current LBP and past history of LBP into true–acute, recurrent, and true–chronic groups. The true–acute group included those with acute onset (≤ 3M) of their current LBP, without a history of LBP. The true–chronic group included those with chronic (> 3M) onset of their current LBP, with a history of continuous LBP leading to their current LBP. The other patients were classified into the recurrent group. Every patient was initially prescribed only oral and/or topical nonsteroidal anti–inflammatory drugs (NSAIDs) regardless of the diagnosis and pain intensity. The ∆VAS–i and ∆VAS–t were significantly larger in the acute group (n=65) than in the chronic group (n=29), and significantly larger in the true–acute group (n=11) than in the true–chronic group (n=12). Our previous study demonstrated that ∆VAS–i and ∆VAS–t in acute LBP are correlated with prognosis and outcome. Acute LBP patients have pain with a large ∆VAS score that reduces rapidly, while chronic LBP patients show a relatively small ∆VAS score and are resistant to NSAIDs. Thus, the present study confirmed the common opinion.

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