Receptor reserve and affinity of mu opioid agonists in mouse antinociception: correlation with receptor binding

Zernig, Gerald; Issaevitch, Tom; Broadbear, Jillian Helen; Burke, T F; Lewis, John W.; Brine, George A.; Woods, James H.

doi:10.1016/0024-3205(95)02204-v

Cited by 38 publications

(38 citation statements)

References 7 publications

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“…However, whereas C-CAM was able to inactivate nearly 100% of the receptor population, the maximal level of receptor inactivation produced by ␤-FNA was 73%, and this was obtained at an intermediate (5.0-mg/ kg) dose. These data are in agreement with previous findings that ␤-FNA can inactivate only 40 to 70% of the -receptor population (Liu-Chen and Phillips, 1987;Franklin and Traynor, 1991), whereas C-CAM can inactivate nearly the entire -receptor population (Burke et al, 1994;Zernig et al, 1995Zernig et al, , 1996a. The explanation for this discrepancy is unclear, although it has been hypothesized that the alkylation produced by ␤-FNA is limited because the dissociation of reversible binding occurs at 5 times the rate of irreversible binding (Liu-Chen et al, 1990).…”

Section: Discussionsupporting

confidence: 93%

Use of Irreversible Antagonists to Determine the Relative Efficacy of μ-Opioids in a Pigeon Drug Discrimination Procedure: Comparison of β-Funaltrexamine and Clocinnamox

Barrett

Smith²,

Picker³

2003

J Pharmacol Exp Ther

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The use of irreversible antagonists to assess opioid efficacy has proven fruitful for classifying opioids on the basis of high or low efficacy, but few studies have provided quantitative estimates of efficacy. The purpose of this study was to use ␤-funaltrexamine (␤-FNA) and clocinnamox (C-CAM) in a drug discrimination procedure to examine the efficacy of fentanyl, morphine, l-methadone, sufentanil, and etorphine. In pigeons trained to discriminate 0.12 mg/kg fentanyl from water, dose-effect curves were determined for each opioid alone and after pretreatment with ␤-FNA and C-CAM. Using quantitative analyses according to an extended model of Black and Leff (1983), apparent efficacy () and affinity (K A ) of each opioid was determined, as well as the degree of receptor inactivation (q) produced by each dose of each antagonist. ␤-FNA and C-CAM produced dose-and time-dependent, rightward shifts in the dose-effect curves of each opioid, and analyses based on dose-ratios and values suggest a rank order of efficacy of etorphine Ͼ sufentanil ϭ l-methadone Ͼ fentanyl ϭ morphine. Marked differences in the profiles of antagonism produced by ␤-FNA and C-CAM were also apparent, as C-CAM, but not ␤-FNA, produced insurmountable antagonism. The q values for each antagonist were consistent with these data in indicating that C-CAM and ␤-FNA can inactivate nearly 100 and 75% of the receptor population, respectively. In tests conducted in pigeons chronically treated with morphine, doses of ␤-FNA that produced parallel, rightward shifts in untreated pigeons flattened the morphine dose-effect curve in morphine-treated pigeons. These results indicate that ␤-FNA and C-CAM can differentiate opioids with high relative efficacy and yield comparable estimates of efficacy for various opioids. There are, however, limitations in the proportion of the receptor population that can by eliminated by ␤-FNA.

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Section: Discussionsupporting

confidence: 93%

Use of Irreversible Antagonists to Determine the Relative Efficacy of μ-Opioids in a Pigeon Drug Discrimination Procedure: Comparison of β-Funaltrexamine and Clocinnamox

Barrett

Smith²,

Picker³

2003

J Pharmacol Exp Ther

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“…In vitro and ex vivo radioligand binding experiments indicate that 24-h pretreatment with 10 mg/kg clocinnamox reduces the B max values for -opioid receptors by 70 to 95% of control values in rats (Paronis and Woods, 1997) and mice (Burke et al, 1994;Zernig et al, 1995Zernig et al, , 1996Chan et al, 1995). A dose of 10 mg/kg clocinnamox yields in vivo estimates of q, the fraction of receptors remaining after inactivation by an insurmountable antagonist (Furchgott, 1966), of approximately 0.10 in the rat warm-water tail-withdrawal assay .…”

Section: Discussionmentioning

confidence: 99%

Clocinnamox Distinguishes Opioid Agonists According to Relative Efficacy in Normal and Morphine-Treated Rats Trained to Discriminate Morphine

Walker

Young²

2002

J Pharmacol Exp Ther

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High doses of insurmountable antagonists or frequent administration of high doses of agonists are required to alter the potency of opioid agonists to produce discriminative stimuli. In the present study, insurmountable antagonism and repeated agonist treatment were combined to remove or disable a large enough proportion of -opioid receptors to alter the potency or maximal effect for four agonists in male Sprague-Dawley rats trained to discriminate 3.2 mg/kg morphine from saline under a fixed-ratio 15 schedule of food reinforcement. All agonists produced 88 to 100% morphine responding and were differentially sensitive to clocinnamox antagonism (fentanyl Ͻ morphine Յ buprenorphine ϭ nalbuphine). Repeated treatment with 20 mg/kg per day morphine for 6 days decreased by 2-to 3-fold the potency of fentanyl, morphine, and buprenorphine to produce morphine responding. After morphine treatment, 3.2 mg/kg clocinnamox produced a 7-fold further decrease in morphine potency. Clocinnamox (10 mg/kg) produced a 7-and 12-fold further decrease in morphine and fentanyl potency, respectively, a reduction in the slope of the morphine doseresponse curve, and a suppression of the maximal morphine responding for buprenorphine. Repeated treatment with 10 mg/kg per day morphine for 6 days failed to alter the potency of nalbuphine to produce morphine responding. In these morphine-treated rats, doses of 3.2 or 10 mg/kg clocinnamox suppressed the maximal morphine responding. Taken together, these data indicate that combined insurmountable antagonist and repeated agonist treatment produce additive effects at -opioid receptors to diminish discriminative stimulus effects in a manner predicted by the relative efficacy of opioid agonists.

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“…opioid receptors elicit similar cellular events (Pan, 1998), the differences of the drug potencies observed here could be interpreted as differences in the affinity/efficacy of the drugs for the various opioid receptors (Zernig et al, 1995;Crooks et al, 2006), as well as different expression of the receptors from physiologically different cell types (Pan, 1998). DAMGO's higher potency to suppress inhibition, compared with morphine, could be accounted for by its higher affinity and efficacy for MORs (Chaturvedi et al, 2000;Crooks et al, 2006) and possibly for the various MOR subtypes (Pasternak, 2001).…”

Section: Figurementioning

confidence: 99%

Effects of μ‐opioid receptor modulation on the hippocampal network activity of sharp wave and ripples

Giannopoulos

Papatheodoropoulos

2013

British J Pharmacology

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BACKGROUND AND PURPOSEHippocampus-dependent memory involves the activity of sharp wave ripples (SWRs), which are thought to participate in the process of memory consolidation. The hippocampus contains high levels of endogenous opioids and of m-opioid receptors (MORs). Here, we have assessed the role of MOR agonists in the modulation of SWRs. EXPERIMENTAL APPROACHUsing recordings of extracellular potentials from the CA1 field of rat hippocampal slices, we examined the pharmacological actions of morphine, DAMGO and fentanyl on SWRs and on network excitability and paired-pulse inhibition. KEY RESULTSAll three MOR agonists (1 nM-10 mM) significantly increased the amplitude of sharp waves and the occurrence of SWR sequences, but reduced the initiation of episodes of SWRs. Fentanyl was most potent in producing these effects and morphine the least. Interestingly, although SWRs were reduced by relatively high concentrations (Ն100 nM) of all agonists, they were significantly enhanced by very low concentrations of morphine (5-10 nM). Morphine and DAMGO at moderate-to-high concentrations increased network excitability and reduced inhibition. Furthermore, DAMGO suppressed inhibition more readily than it increased excitation, whereas morphine suppressed inhibition only at high concentrations. These drug effects were reversed by the MOR antagonists naloxone and CTOP. CONCLUSIONS AND IMPLICATIONSWe found that the SWRs were significantly modulated by three MOR agonists and that the SWRs were very sensitive to subtle changes in the excitation/inhibition balance induced by MOR agonists. Such modulation might underlie the effects of these agonists on hippocampus-dependent memory. AbbreviationsICI, intra-cluster interval; IEI, inter-event interval; IEpI, inter-episode interval; MOR, m-opioid receptor; PPI, paired-pulse inhibition; PS, population spike; SWR, sharp wave ripple BJP British Journal of Pharmacology DOI:10.1111DOI:10. /j.1476DOI:10. -5381.2012 1146 British Journal of Pharmacology (2013) IntroductionEndogenous and clinically administered opioids act on many receptors (Waldhoer et al., 2004) and are involved in a wide variety of functions (Drolet et al., 2001) including hippocampus-dependent learning and memory (Wise, 1989;Meilandt et al., 2004;Bodnar, 2010;Kesner and Warthen, 2010;Dacher and Nugent, 2011). Nevertheless, the mechanisms by which opioids affect hippocampus-dependent memory appear to be highly complex and poorly understood.The critical involvement of the hippocampus in learning and memory (Eichenbaum, 2004;Squire et al., 2004) is underpinned by a number of different types of neuronal activity supporting distinct processes (Battaglia et al., 2011). For example, it is assumed that the encoding of new information that occurs during active behaviour is associated with q oscillation (Hasselmo, 2005) whereas memory consolidation takes place during inactivity (Alvarez and Squire, 1994;McGaugh, 2000). It is generally thought that memory consolidation entails the generation of irregular activity of sharp wave ripples...

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Receptor reserve and affinity of mu opioid agonists in mouse antinociception: correlation with receptor binding

Cited by 38 publications

References 7 publications

Use of Irreversible Antagonists to Determine the Relative Efficacy of μ-Opioids in a Pigeon Drug Discrimination Procedure: Comparison of β-Funaltrexamine and Clocinnamox

Use of Irreversible Antagonists to Determine the Relative Efficacy of μ-Opioids in a Pigeon Drug Discrimination Procedure: Comparison of β-Funaltrexamine and Clocinnamox

Clocinnamox Distinguishes Opioid Agonists According to Relative Efficacy in Normal and Morphine-Treated Rats Trained to Discriminate Morphine

Effects of μ‐opioid receptor modulation on the hippocampal network activity of sharp wave and ripples

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