Blockade of tolerance to morphine but not to kappa opioids by a nitric oxide synthase inhibitor.

Kolesnikov, Yuri; Pick, Chaim G.; Ciszewska, Grazyna; Pasternak, Gavril W.

doi:10.1073/pnas.90.11.5162

Cited by 244 publications

(138 citation statements)

References 28 publications

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“…Our finding is consistent with the observation that although the NO synthase inhibitor NMLA prevents morphine tolerance, acutely it does prevent expression of tolerance (Kolesnikov et al, 1993;L ondon et al, 1995;Dambisya and Lee, 1996;Dunbar and Yaksh, 1996). Interestingly, although mechanisms of development are distinct for tolerance and dependence, there are some common mechanisms of expression, namely calcium.…”

Section: Discussionsupporting

confidence: 81%

Different Mechanisms Mediate Development and Expression of Tolerance and Dependence for Peripheral μ-Opioid Antinociception in Rat

Aley

Levine

1997

J. Neurosci.

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The -opioid [D-Ala 2 ,N-Me-Phe 4 ,Gly-ol 5 ]-enkephalin (DAMGO) exerts a peripheral antinociceptive effect against prostaglandin E 2 (PGE 2 )-induced mechanical hyperalgesia in the hindpaw of the rat. Tolerance and dependence develop to this effect. We have shown previously that tolerance and dependence can be dissociated and are mediated by different second messenger systems. In the present study, we evaluated whether the same or different second messenger systems mediate the development of this peripheral opioid tolerance or dependence compared with the expression of the loss of antinociceptive effect or rebound opioid antagonist hyperalgesia (i.e., expression of tolerance and dependence). DAMGO-induced tolerance was prevented by pretreatment with the nitric oxide synthase inhibitor N G -methyl-L-arginine (NMLA) but not by the protein kinase C (PKC) inhibitor chelerythrine, the adenylyl cyclase inhibitor 2Ј,5Ј-dideoxyadenosine (ddA), or the calcium chelators 3,4,5-trimethoxybenzoic acid 8-(diethylamino)-octyl ester (TMB-8) and 2-[(2-bis-[carboxymethyl]amino-5-methylphenoxy)-methyl]-6-methoxy-8-bis[carboxymethyl]aminoquinoline (Quin-2).Once established, however, expression of DAMGO tolerance was acutely reversed by TMB-8 or Quin-2 but not by chelerythrine or NMLA. In contrast, naloxone-precipitated hyperalgesia in DAMGO-tolerant paws, a measure of dependence, was blocked by pretreatment with chelerythrine but not by NMLA, ddA, TMB-8, or Quin-2. Naloxone-precipitated hyperalgesia in DAMGO-tolerant paws was acutely reversed by chelerythrine, ddA, TMB-8, or Quin-2 but not by NMLA. Taken together, these results provide the first evidence that different mechanisms mediate the development and expression of both tolerance and dependence to the peripheral antinociceptive effect of DAMGO. However, although the development of tolerance and dependence are entirely separable, the expression of tolerance and dependence shares common calcium-dependent mechanisms. Opioids, which traditionally are thought to produce analgesia by actions in the C NS, also have antinociceptive actions in the periphery (Levine and Taiwo, 1989;Stein, 1991;Stein et al., 1995). Peripheral analgesic effects of opioids seem to be mediated via -opioid receptors and a G i -and G o -protein-mediated inhibition of the cAM P second messenger system in primary afferent nociceptors (Levine and Taiwo, 1989). We and others have reported previously that tolerance and dependence develop for this peripheral antinociceptive effect of -opioid agonists (Aley et al., 1995;Kolesnikov et al., 1996). In the C NS a number of intracellular pathways have been suggested to play a role in opioid tolerance and dependence (Honore et al., 1997). Among these, Ca 2ϩ (Wang et al., 1996), protein kinase C (Mao et al., 1995a,b;Narita et al., 1995), and nitric oxide (Herman et al., 1995;Pasternak et al., 1995;Vaupel et al., 1995;Dambisya and Lee, 1996;Dunbar and Yaksh, 1996) have been most thoroughly implicated. The mechanisms underlying peripheral opioid tolerance and dependence are...

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Section: Discussionsupporting

confidence: 81%

Different Mechanisms Mediate Development and Expression of Tolerance and Dependence for Peripheral μ-Opioid Antinociception in Rat

Aley

Levine

1997

J. Neurosci.

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“…3A and Fig. S1), ∼10-fold more potent than morphine (4.6 ± 0.97 mg/kg s.c.) (10), with a mechanism of action quite distinct from traditional opiates. It was active s.c. as well as orally (Fig.…”

Section: Resultsmentioning

confidence: 99%

Truncated G protein-coupled mu opioid receptor MOR-1 splice variants are targets for highly potent opioid analgesics lacking side effects

Majumdar

Grinnell

Rouzic

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

138

257

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Pain remains a pervasive problem throughout medicine, transcending all specialty boundaries. Despite the extraordinary insights into pain and its mechanisms over the past few decades, few advances have been made with analgesics. Most pain remains treated by opiates, which have significant side effects that limit their utility. We now describe a potent opiate analgesic lacking the traditional side effects associated with classical opiates, including respiratory depression, significant constipation, physical dependence, and, perhaps most important, reinforcing behavior, demonstrating that it is possible to dissociate side effects from analgesia. Evidence indicates that this agent acts through a truncated, six-transmembrane variant of the G protein-coupled mu opioid receptor MOR-1. Although truncated splice variants have been reported for a number of G protein-coupled receptors, their functional relevance has been unclear. Our evidence now suggests that truncated variants can be physiologically important through heterodimerization, even when inactive alone, and can comprise new therapeutic targets, as illustrated by our unique opioid analgesics with a vastly improved pharmacological profile.opiate receptor | rewarding behavior | kappa 3 receptor T he utility of opioids in the management of pain is not disputed, but they come at a price. Along with their ability to relieve pain comes a variety of opioid receptor-mediated side effects, including respiratory depression, constipation, physical dependence, and reward behavior felt by many to contribute to their addictive potential. Most of the clinical opioids act through mu receptors, which mediate both analgesia and these side effects. Pharmacological studies have long suggested subtypes of mu receptors (1) and the possibility of dissociating analgesia from respiratory depression (2, 3), physical dependence (4), and the inhibition of gastrointestinal transit (5, 6). However, attempts to develop opiate analgesics that avoid these side effects have not been very fruitful. The isolation of a series of splice variants of the cloned mu opioid receptor from mice ( Fig. 1), rats, and humans with similar splicing patterns (7, 8) reveals a complexity far exceeding the pharmacological classification of mu receptor subtypes (1). However, this complexity has yet to be exploited in generating new classes of opioid analgesics. We now report an unexpected and unusual target for potent opioid analgesic drugs that lack respiratory depression, physical dependence, reward behavior, and significant constipation. ResultsRecently, we synthesized iodobenzoylnaltrexamide (IBNtxA), a naltrexone derivative (Fig. 2) (9). In vivo, it is a very potent analgesic (ED 50 = 0.48 ± 0.05 mg/kg s.c.) (Fig. 3A and Fig. S1), ∼10-fold more potent than morphine (4.6 ± 0.97 mg/kg s.c.) (10), with a mechanism of action quite distinct from traditional opiates. It was active s.c. as well as orally (Fig. S1), with a peak effect after oral administration that was delayed relative to parenteral administration. In ...

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“…Evidence from previous studies has implicated the nNOS-NO pathway in the modulation of CNSmediated drug effects. Thus, inhibition of NOS has been shown to influence the development of tolerance (Khanna et al, 1993(Khanna et al, , 1995Kolesnikov et al, 1993Kolesnikov et al, , 1997 and sensitization (Itzhak et al, 1998;Itzhak and Martin, 2000) to several drugs of abuse, including alcohol. Beside these findings, two other lines of evidence have prompted us to study the role of the nNOS gene in the regulation of neurobehavioral effects of alcohol:…”

Section: Abstract: Neuronal Nitric Oxide Synthase; Nnos; Nnos Splicementioning

confidence: 99%

The Neuronal Nitric Oxide Synthase Gene Is Critically Involved in Neurobehavioral Effects of Alcohol

et al. 2002

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In the present study, we describe a new role of the neuronal nitric oxide synthase (nNOS) gene in the regulation of alcohol drinking behavior. Mice deficient in the nNOS gene (nNOS Ϫ/Ϫ) and wild-type control mice were submitted to a two-bottle free-choice procedure with either water or increasing concentrations of alcohol (2-16%) for 6 weeks. nNOS Ϫ/Ϫ mice did not differ in consumption and preference for low alcohol concentrations from wild-type animals; however, nNOS Ϫ/Ϫ mice consumed sixfold more alcohol from highly concentrated alcohol solutions than wild-type mice. Taste studies with either sucrose or quinine solutions revealed that alcohol intake in nNOS Ϫ/Ϫ and wild-type mice is associated, at least in part, with sweet solution intake but not with the taste of bitterness. When compared with wild-type mice, the nNOS Ϫ/Ϫ mice were found to be less sensitive to the sedative effects of ethanol as measured by shorter recovery time from ethanol-induced sleep and did not develop rapid tolerance to ethanol-induced hypothermia, although plasma ethanol concentrations were not significantly different from those of controls. Our findings contrast with previous reports that showed that nonselective NOS inhibitors decrease alcohol consumption. However, because alcohol consumption was suppressed in wild-type as well as nNOS Ϫ/Ϫ mice by the NOS inhibitor N G -nitro-L-arginine methyl ester, we conclude that the effect of nonselective NOS inhibitors on alcohol drinking is not mediated by nNOS. Other NOS isoforms, most likely in the periphery or other splice variants of the NOS gene, might contribute to the effect of nonselective NOS inhibitors on alcohol drinking. In summary, the nNOS gene is critically involved in the regulation of neurobehavioral effects of alcohol.

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Blockade of tolerance to morphine but not to kappa opioids by a nitric oxide synthase inhibitor.

Cited by 244 publications

References 28 publications

Different Mechanisms Mediate Development and Expression of Tolerance and Dependence for Peripheral μ-Opioid Antinociception in Rat

Different Mechanisms Mediate Development and Expression of Tolerance and Dependence for Peripheral μ-Opioid Antinociception in Rat

Truncated G protein-coupled mu opioid receptor MOR-1 splice variants are targets for highly potent opioid analgesics lacking side effects

The Neuronal Nitric Oxide Synthase Gene Is Critically Involved in Neurobehavioral Effects of Alcohol

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