Background and purpose: Buprenorphine displays attributes of opioids, but also some features distinct from them. We examined spinal and supraspinal signal transduction of buprenorphine-induced anti-nociception in mice compared with morphine and fentanyl. Experimental approach: The opioid receptor antagonist naloxone, Pertussis toxin (PTX), Gz protein antisense and nociceptin/ orphanin-FQ receptor agonist nociceptin, and antagonist, JTC-801, were injected supraspinally (intracerebroventricular) and spinally (intrathecal). Also the cell-permeable Ser/Thr protein phosphatase inhibitor okadaic acid was given supraspinally. Key results: Spinal naloxone (20 mg) or PTX (1 mg) attenuated morphine, fentanyl and buprenorphine (s.c.) anti-nociception. Supraspinal naloxone or PTX attenuated morphine and fentanyl, but not buprenorphine anti-nociception. Spinal Gz protein antisense did not alter buprenorphine, morphine or fentanyl anti-nociception and supraspinal Gz-antisense did not alter morphine or fentanyl anti-nociception. However, supraspinal Gz-antisense (not random sense) reduced buprenorphine antinociception. Peripheral JTC-801 (1 mg·kg -1 , i.p.) enhanced the ascending (3 mg·kg -1 ) and descending (30 mg·kg -1 ) portions of buprenorphine's dose-response curve, but only spinal, not supraspinal, nociceptin (10 nmol·L -1 ) enhanced buprenorphine anti-nociception. Intracereboventricular okadaic acid (0.001-10 pg) produced a biphasic low-dose attenuation, high-dose enhancement of buprenorphine(3 or 30 mg·kg -1 , s.c.) anti-nociception, but did not affect morphine or fentanyl anti-nociception. Conclusions and implications:Buprenorphine has an opioid component to its supraspinal mechanism of analgesic action. Our present results reveal an additional supraspinal component insensitive to naloxone, PTX and nociceptin/orphanin-FQ, but involving Gz protein and Ser/Thr protein phosphatase. These data might help explain the unique preclinical and clinical profiles of buprenorphine.

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We previously showed that Na ؉ /H ؉ -exchanger regulatory factor-1/Ezrin-radixin-moesin-binding phosphoprotein-50 (NHERF-1/EBP50) co-immunoprecipitated with the human opioid receptor (hKOR) and that its overexpression blocked the agonist U50,488H-induced hKOR down-regulation by enhancing recycling. Here, we show that glutathione S-transferase (GST)-hKOR Ctail interacted with purified NHERF-1/EBP50, whereas GST or GST-C-tails of or ␦ opioid receptors did not. GST-hKOR C-tail The opioid receptor (KOR)1 is one of the multiple types (at least , ␦, and ) of opioid receptors that mediate pharmacological effects of opioid drugs and physiological actions of endogenous peptides. Activation of opioid receptors in vivo results in many effects, including analgesia (1-3), dysphoria (2-4), and water diuresis (1, 2). At cellular levels, stimulation of opioid receptors activates G i /G o proteins resulting in downstream changes, such as inhibition of adenylyl cyclase, activation of p42/p44 mitogen-activated protein (MAP) kinase, increase in K ϩ conductance, and decrease in Ca 2ϩ conductance (for a review, see Ref. 5). opioid receptors of the human, rat, mouse, and guinea pig have been cloned (for reviews, see Refs. 6 and 7), and the receptors belong to the rhodopsin subfamily of G protein-coupled receptors (GPCRs) (8).PDZ domains were originally identified in the proteins postsynaptic density-95 (PSD-95), discs-large, and zona occludens-1 (ZO-1) as repeats of about 90 amino acids containing the conserved motif Gly-Leu-Gly-Phe. These domains mediate protein-protein interactions by interacting with the last few Cterminal residues of their target proteins (9, 10). Many GPCRs have been shown to interact with PDZ domain-containing proteins, and such interactions play important roles in signal transduction and receptor regulation (for a review, see Ref. 11). Na ϩ /H ϩ exchanger regulatory factor-1 (NHERF-1)/ezrin-radixin-moesin (ERM)-binding phosphoprotein-50 (EBP50) is a PDZ domain-containing protein. Rabbit NHERF-1 was first purified and cloned (12), and the human homolog was subsequently cloned, termed EBP50 (13) or hNHERF (14). The term

Transient forebrain or global ischemia induces neuronal death in vulnerable CA1 pyramidal cells with many features. A brief period of ischemia, i.e., ischemic preconditioning, or a modified reperfusion such as ischemic postconditioning, can afford robust protection of CA1 neurons against ischemic challenge. Therefore, we investigated the effect of ischemic preconditioning and postconditioning on neural cell apoptosis in rats. The result showed that both ischemic preconditioning and postconditioning may attenuate the neural cell death and DNA fragment in the hippocampal CA1 region. Further western blot study suggested that ischemic preconditioning and postconditioning down-regulates the protein of cleaved caspase-3, caspase-6, caspase-9 and Bax, but up-regulates the protein Bcl-2. These findings suggest that ischemic preconditioning and postconditioning have a neuroprotective role on global brain ischemia in rats through the same effect on inhibition of apoptosis.

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