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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