Blockade of the development of morphine tolerance by U‐50,488, an AVP antagonist or MK‐801 in the rat hippocampal slice

Abstract

1 In this study, we investigated the eects of dierent drugs (a k-opioid receptor agonist U-50,488, a vasopressin receptor antagonist dPTyr(Me)AVP or an N-methyl-D-aspartate (NMDA) receptor antagonist MK-801) on the development of morphine tolerance in rat hippocampal slices. 2 Hippocampal slices (450 mm) of Sprague-Dawley rats (250 ± 300 g) were used. Slices were continuously superfused with arti®cial CSF or drugs at 1 ml min 71 . Nichrome wire electrodes were placed in the Schaer-collateral pathway and used to deliver biphasic 0.2 ms pulses of 5 ± 30 V (0.033 Hz). A glass microelectrode was placed in the CA1 area to record population spikes. 3 When the slices were superfused with 10 mM morphine, the amplitude of population spikes increased 2 ± 3 fold in 30 ± 40 min. However, this eect of morphine decreased, i.e. tolerance developed after continuous superfusion of morphine for 2 ± 6 h. 4 When either U-50,488 (200 nM) or dPTyr(Me) AVP (500 pM) or MK-801 (500 pM) was cosuperfused with morphine (10 mM), it signi®cantly blocked the development of morphine tolerance. Nor-BNI (a k-opioid receptor antagonist, 200 nM) signi®cantly reversed the inhibitory eect of U-50,488 but not those of dPTyr(Me)AVP or MK-801 on the development of morphine tolerance. 5 These data indicate that k-opioid receptors, AVP receptors and NMDA receptors are all involved in the development of morphine tolerance. The suppression of k-opioid receptor activity after chronic morphine may occur before the activation of AVP receptors or NMDA receptors during the development of morphine tolerance.

Are NMDA receptors involved in opiate-induced neural and behavioral plasticity?

“…MK-801 inhibited the development of tolerance, as reflected in analgesia, and prevented the increase in protein kinase C, demonstrating a nice correlation between changes in behavior and neurochemistry. Additional studies have explored cellular changes in the spinal cord (Wong et al 1996;Le Guen et al 1999), which may have relevance to tolerance to the analgesic effect of opiates, as well as specific brain regions (Trujillo et al 1991;Garcia and Harlan 1993;Makimura et al 1996Makimura et al , 1997Su et al 1998), which may have relevance to other aspects of opiate tolerance, sensitization or physical dependence (Table 4). Together, these studies demonstrate 1) that the development of opiate tolerance, sensitization and physical dependence are accompanied by cellular changes in the brain and spinal cord that may reflect the neural plasticity underlying the behavioral changes, and 2) that these cellular changes can be inhibited by NMDA receptor antagonists in a manner that parallels the behavioral changes.…”

“…Comp and protein kinase C in pons/medulla (tolerance); Withdrawal-induced increase in norepinephrine release in hippocampus (dependence) Su et al (1998) MK-801 Non-comp Rat Morphine-induced increase in population spike amplitude hippocampal in hippocampus (tolerance) slice Le Guen et al (1999) MK-801 Non-comp Rat Morphine suppression of carageenin-induced c-Fos LY 235959 Comp expression in spinal cord (tolerance) phine-induced effects. A second study of note is that of Bilsky and coworkers (1996).…”

Involvement of kappa opioid receptors in the inhibition of receptor desensitization and PKC activation induced by repeated morphine treatment

“…In response to analgesic tolerance caused by repeated administration of morphine, KOR agonists such as U-50488H (Tao et al 2000;Tokuyama et al 2007) and dynorphin (Brugos et al 2004) inhibit the development of tolerance at a dose at which no analgesic effect is observed. Moreover, this inhibitory effect was antagonized by nor-binaltorphimine (nor-BNI), a KOR antagonist, suggesting that KOR plays an important role in the mechanism of inhibition of morphine tolerance (Su et al 1998). Our previous data have also shown that inhibition of morphine tolerance under chronic pain conditions is blocked by antisense oligodeoxynucleotide directed against KOR (Tokuyama et al 2007).…”

Dextromethorphan differentially affects opioid antinociception in rats

“…Nalbuphine was purchased from Mallinckrodt Inc. (St Louis, Missouri, U.S.A.). U‐50,488H was a gift from Dr Chen‐Yu Cheng, who prepared it as described in our previous paper (Su et al ., 1998). All other chemicals were supplied by Sigma (St Louis, MO, U.S.A.).…”