Ligand-biased activation of extracellular signal-regulated kinase 1/2 leads to differences in opioid induced antinociception and tolerance

Bobeck, Erin N.; Ingram, Susan; Hermes, Sam M.; Aicher, Sue A.; Morgan, Michael M.

doi:10.1016/j.bbr.2015.10.032

Cited by 17 publications

(14 citation statements)

References 57 publications

(85 reference statements)

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“…RGS proteins are defined by their ability to facilitate inactivation of G-protein signalling following GPCR activation. The enhanced morphine antinociception resulting from facilitation of G-protein signalling is consistent with previous research showing that pertussis toxin-induced inhibition of G-protein signalling in the PAG disrupts morphine, but not fentanyl antinociception (Bobeck et al, 2016;Bodnar et al, 1990).…”

Section: Discussionsupporting

confidence: 91%

Differences in antinociceptive signalling mechanisms following morphine and fentanyl microinjections into the rat periaqueductal gray

Morgan

Tran

Wescom

et al. 2019

European Journal of Pain

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Background Morphine and fentanyl are two of the most commonly used opioids to treat pain. Although both opioids produce antinociception by binding to mu‐opioid receptors (MOR), they appear to act via distinct signalling pathways. Objective This study will reveal whether differences in morphine and fentanyl antinociception are the result of selective activation of G‐protein signalling and/or selective activation of pre‐ or postsynaptic MORs. Methods The contribution of each mechanism to morphine and fentanyl antinociception was assessed by microinjecting drugs to alter G‐protein signalling or block potassium channels linked to pre‐ and postsynaptic MORs in the ventrolateral periaqueductal gray (PAG) of male Sprague‐Dawley rats. Results Both morphine and fentanyl produced a dose‐dependent antinociception when microinjected into the PAG. Enhancement of intracellular G‐protein signalling by microinjection of the Regulator of G‐protein Signalling 4 antagonist CCG‐63802 into the PAG enhanced the antinociceptive potency of morphine, but not fentanyl. Microinjection of α‐dendrotoxin into the PAG to block MOR activation of presynaptic Kv+ channels caused a significant rightward shift in the dose–response curve of both morphine and fentanyl. Microinjection of tertiapin‐Q to block MOR activation of postsynaptic GIRK channels caused a larger shift in the dose–response curve for fentanyl than morphine antinociception. Conclusions These findings reveal different PAG signalling mechanisms for morphine and fentanyl antinociception. In contrast with fentanyl, the antinociceptive effects of morphine are mediated by G‐protein signalling primarily activated by presynaptic MORs. Significance Microinjection of the opioids morphine and fentanyl into the periaqueductal gray (PAG) produce antinociception via mu‐opioid receptor signalling. This study reveals differences in the signalling mechanisms underlying morphine and fentanyl antinociception in the PAG. In contrast with fentanyl, morphine antinociception is primarily mediated by presynaptic opioid receptors and is enhanced by blocking RGS proteins.

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Section: Discussionsupporting

confidence: 91%

Differences in antinociceptive signalling mechanisms following morphine and fentanyl microinjections into the rat periaqueductal gray

Morgan

Tran

Wescom

et al. 2019

European Journal of Pain

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“…In conclusion, morphine-induced hyperalgesia was absent in MOR KO mice, highlighting MOR requirement on OIH. Taken together, the present and previous studies suggest a role for specific MOR populations 26 , 61 , 63 , isoforms 33 or signalling 64 at some nervous system sites that require further investigation.…”

Section: Discussionsupporting

confidence: 77%

Morphine-induced hyperalgesia involves mu opioid receptors and the metabolite morphine-3-glucuronide

Roeckel

Utard

Reiss

et al. 2017

Sci Rep

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Opiates are potent analgesics but their clinical use is limited by side effects including analgesic tolerance and opioid-induced hyperalgesia (OIH). The Opiates produce analgesia and other adverse effects through activation of the mu opioid receptor (MOR) encoded by the Oprm1 gene. However, MOR and morphine metabolism involvement in OIH have been little explored. Hence, we examined MOR contribution to OIH by comparing morphine-induced hyperalgesia in wild type (WT) and MOR knockout (KO) mice. We found that repeated morphine administration led to analgesic tolerance and hyperalgesia in WT mice but not in MOR KO mice. The absence of OIH in MOR KO mice was found in both sexes, in two KO global mutant lines, and for mechanical, heat and cold pain modalities. In addition, the morphine metabolite morphine-3beta-D-glucuronide (M3G) elicited hyperalgesia in WT but not in MOR KO animals, as well as in both MOR flox and MOR-Nav1.8 sensory neuron conditional KO mice. M3G displayed significant binding to MOR and G-protein activation when using membranes from MOR-transfected cells or WT mice but not from MOR KO mice. Collectively our results show that MOR is involved in hyperalgesia induced by chronic morphine and its metabolite M3G.

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“…Blockade of a component of β-arrestin signaling (i.e. G-protein receptor kinase or extracellular signal regulated kinase) has been shown to prevent tolerance to agonists, such as fentanyl, and have no effect on tolerance to morphine 2,16,21,26,32 . In contrast, inhibition of proteins downstream of G-protein signaling (i.e.…”

Section: Discussionmentioning

confidence: 99%

Lack of Antinociceptive Cross-Tolerance With Co-Administration of Morphine and Fentanyl Into the Periaqueductal Gray of Male Sprague-Dawley Rats

Bobeck

Schoo

Ingram

et al. 2019

The Journal of Pain

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Tolerance to the antinociceptive effect of mu-opioid receptor (MOPr) agonists, such as morphine and fentanyl, greatly limits their effectiveness for long-term use to treat pain. Clinical studies have shown that combination therapy and opioid rotation can be used to enhance opioid-induced antinociception once tolerance has developed. The mechanism and brain regions involved in these processes are unknown. The purpose of this study was to evaluate the contribution of the ventrolateral periaqueductal gray (vlPAG) to antinociceptive tolerance and cross-tolerance between administration and coadministration of morphine and fentanyl. Tolerance was induced by pretreating rats with morphine or fentanyl or low-dose combination of morphine and fentanyl into the vlPAG followed by assessment of cross-tolerance to the other opioid. In addition, tolerance to the combined treatment was assessed. Cross-tolerance did not develop between repeated vlPAG microinjections of morphine and fentanyl. Likewise, there was no evidence of cross-tolerance from morphine or fentanyl to co-administration of morphine and fentanyl. Co-administration did not cause cross-tolerance to fentanyl. Crosstolerance was only evident to morphine or morphine and fentanyl combined in rats pretreated with co-administration of low-doses of morphine and fentanyl. In conclusion, cross-tolerance does not develop between morphine and fentanyl within the vlPAG. This finding is consistent with the functionally selective signaling that has been reported for antinociception and tolerance following morphine and fentanyl binding to the MOPr. This research supports the notion that combination therapy and opioid rotation may be useful clinical practices to reduce opioid tolerance and other side effects. Perspective: This preclinical study shows that there is a reduction in cross tolerance between morphine and fentanyl within the periaqueductal gray which is key brain region in opioid antinociception and tolerance.

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Ligand-biased activation of extracellular signal-regulated kinase 1/2 leads to differences in opioid induced antinociception and tolerance

Cited by 17 publications

References 57 publications

Differences in antinociceptive signalling mechanisms following morphine and fentanyl microinjections into the rat periaqueductal gray

Differences in antinociceptive signalling mechanisms following morphine and fentanyl microinjections into the rat periaqueductal gray

Morphine-induced hyperalgesia involves mu opioid receptors and the metabolite morphine-3-glucuronide

Lack of Antinociceptive Cross-Tolerance With Co-Administration of Morphine and Fentanyl Into the Periaqueductal Gray of Male Sprague-Dawley Rats

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