Buprenorphine is a mixed opioid receptor agonist-antagonist. Recently, buprenorphine was reported to act as an agonist to opioid receptor like-1 (ORL1) receptor. In the present study, we examined the role of spinal and supraspinal receptors and spinal and supraspinal ORL1 receptors in producing an analgesic effect by intrathecal (i.t.), intracerebroventricular (i.c.v.), or i.p. administration of buprenorphine in the rat formalin test. Male rats were prepared with i.t. catheters or i.c.v. injection cannulas. The paw formalin injection (50 l of 5% formalin) induces biphasic flinching (phase 1, 0 -6 min; phase 2, 10 -60 min) of the injected paw. Buprenorphine, naloxone (a -opioid Buprenorphine is a derivative of the morphine alkaloid thebaine and is used for the treatment of moderate to severe pain (Johnson et al., 2005). Buprenorphine has been reported to have high affinities for -, -, and ␦-opioid receptors with K i values in the nanomolar range. (Huang et al., 2001).Recently, buprenorphine has been reported to act as an agonist at opioid receptor like-1 (ORL1) receptors (BlomsFunke et al., 2000). Lutfy et al. (2003) reported that the antinociceptive effect of subcutaneously administered buprenorphine was markedly enhanced in mice lacking ORL1 receptors in the tail-flick test and that systemic administration of an ORL1 receptor antagonist enhanced the analgesic effect of s.c. administered buprenorphine. Mice lacking -opioid receptors failed to exhibit an antinociceptive effect after s.c. administration of buprenorphine (Lutfy et al., 2003).Moreover, buprenorphine did not produce an analgesic effect in 1 -opioid receptor-deficient mice (Kamei et al., 1997). These data suggest that the antinociceptive effect of systemically administered buprenorphine is mediated by the activation of -opioid receptors and that the analgesic effect of systemically administered buprenorphine is suppressed by concomitant activation of ORL1 receptors. On the other hand, spinal ORL1 receptor activation has been reported to produce an analgesic effect (Yamamoto et al., 1997(Yamamoto et al., , 1999).-Opioid receptors and ORL1 receptors are widely located in the nervous system, and there are not enough data to determine which -opioid receptor plays an important role in producing an analgesic effect of buprenorphine and which ORL1 receptor plays an important role in suppressing an analgesic effect of buprenorphine when buprenorphine is administered systemically. Moreover, it is possible that the analgesic effect of systemically administered buprenorphine can be attributed to the activation of spinal ORL1 receptors. In the present study, we investigated the analgesic effect of intrathecal (i.t.), intracerebroventricular (i.c.v.), or i.p. ad-

Morphine is a potent analgesic, but the molecular mechanism for tolerance formation after repeated use is not fully understood. Binding immunoglobulin protein (BiP) is an endoplasmic reticulum (ER) chaperone that is central to ER function. We examined knock-in mice expressing a mutant BiP with the retrieval sequence deleted in order to elucidate physiological processes that are sensitive to BiP functions. We tested the thermal antinociceptive effect of morphine in heterozygous mutant BiP mice in a hot plate test. Paw withdrawal latencies before and after a single administration of morphine were not significantly different between the wild-type and mutant BiP mice. Repeated morphine administration caused the development of morphine tolerance in the wild-type mice. The activation of glycogen synthase kinase 3b (GSK-3b) was associated with morphine tolerance, because an inhibitor of GSK-3β prevented it. On the other hand, the mutant BiP mice showed less morphine tolerance, and the activation of GSK-3b was suppressed in their brain. These results suggest that BiP may play an important role in the development of morphine tolerance. Furthermore, we found that a chemical chaperone which improves ER protein folding capacity also attenuated the development of morphine tolerance in wild-type mice, suggesting a possible clinical application of chemical chaperones in preventing morphine tolerance.

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Aim Pregnancy with myasthenia gravis (MG) is known to be associated with an increased cesarean section rate, presumably due to maternal fatigue during labor. Although epidural labor analgesia (ELA) appears to be a good option for circumventing maternal fatigue, a protocol for managing MG deliveries has not been established. This study, based on a review of our case series, aimed to evaluate the validity of our management protocol for maternal MG, in which ELA is used depending on MG severity. Methods Parturients with systemic muscle weakness or worsening symptoms were classified as Category A (A), and those without symptoms were classified as Category B (B). In A, ELA was given at the onset of labor. Immediate vacuum delivery was done once the fetal head descended to station +2. For B, spontaneous vaginal delivery was chosen. The duration, blood loss, fetal weight, Apgar score and MG symptoms on post‐partum day (PPD) 1, 14 and 30 were recorded. Results Six patients were enrolled. Four were classified in A, and two were classified in B. No adverse events occurred during labor. Transvaginal delivery was successfully achieved in all the patients. Symptoms of MG were well‐controlled. MG symptoms were stable on PPD 1 in all the patients although two patients complained of worsening symptoms after PPD 14. Conclusion Women with MG can safely undergo spontaneous or operative vaginal delivery. ELA is a good option for circumventing the effects of maternal fatigue on delivery. Our protocol may lower the cesarean section rate in maternal MG.

ObjectiveThe present trial aimed to prove the non‐inferiority of the analgesic efficacy of continuous wound infiltration (CWI) to that of continuous intravenous fentanyl (IV) and to compare the safety of the two methods.MethodsThis trial was a prospective, single‐centre, two‐arm, non‐inferiority, randomised controlled trial. Patients participating in the trial were randomised to a CWI group or an IV group. The VAS (visual analogue scale), additional analgesic usage and side effects were then compared between the groups.ResultsIn total, 61 patients were enrolled; two in CWI were excluded, leaving 59 (30 in the CWI group and 29 in the IV group) for analysis. The difference in the VAS score at 24 h (CWI group – IV group) was −3.2 (95% confidence interval [CI] −14.7 to 8.2), which was less than the non‐inferiority margin of 15. The mean amount of total fentanyl use at postoperative hour 48 was 1395 (95% CI 886–1903) µg in the CWI group and 3186 (95% CI 2716–3658) µg in the IV group. The amount of other analgesics and the incidence of adverse effects did not differ significantly between the groups.ConclusionCWI was non‐inferior to IV in terms of its analgesic effect, and has an opioid sparing effect in open gynaecological surgery.

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