[35S]GTPγS binding and opioid tolerance and efficacy in mouse spinal cord

Madia, Priyanka A.; Navani, Dipesh; Yoburn, Byron C.

doi:10.1016/j.pbb.2011.11.001

Cited by 20 publications

(27 citation statements)

References 44 publications

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“…; Madia et al . ), the differential intracellular trafficking of C‐terminal splice variants, per se, is not likely to be a primary factor modulating morphine analgesic tolerance in vivo .…”

Section: Discussionmentioning

confidence: 98%

Mu‐opioid receptor splice variants: sex‐dependent regulation by chronic morphine

Verzillo

Madia

Liu

et al. 2014

Journal of Neurochemistry

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The gene encoding the mu-opioid receptor (MOR) generates a remarkable diversity of subtypes, the functional significance of which remains largely unknown. The structure of MOR could be a critical determinant of MOR functionality and its adaptations to chronic morphine exposure. Since MOR antinociception has sexually dimorphic dimensions, we determined the influence of sex, stage of estrus cycle and chronic systemic morphine on levels of MOR splice variant mRNA in rat spinal cord. Chronic systemic morphine influenced the spinal expression of mRNA encoding rMOR-1B2 and rMOR-1C1 in a profoundly sex-dependent fashion. In males, chronic morphine resulted in a 2-fold increase in expression levels of rMOR-1B2 and rMOR-1C1 mRNA. This effect of chronic morphine was completely absent in females. Increased density of MOR protein in spinal cord of males accompanied the chronic morphine-induced increase in MOR variant mRNA, suggesting that it reflected an increase in corresponding receptor protein. These results suggest that tolerance/dependence results, at least in part, from different adaptational strategies in males and females. The signaling consequences of the unique composition of the C-terminus tip of rMOR-1C1 and rMOR-1B2 could point the way to defining the molecular components of sex-dependent tolerance and withdrawal mechanisms.

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Section: Discussionmentioning

confidence: 98%

Mu‐opioid receptor splice variants: sex‐dependent regulation by chronic morphine

Verzillo

Madia

Liu

et al. 2014

Journal of Neurochemistry

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“…Taken together these results within the vlPAG are consistent with previous studies evaluating the role of Gα i/o proteins on antinociception using intracerebroventricular administration. Blockade of Gα i/o proteins with PTX or antisense oligodeoxynucleotides produced a ligand biased attenuation of antinociception in the order of morphine > DAMGO > sufentanil (a fentanyl analog) (Raffa et al, 1994, Goode and Raffa, 1997), which inversely correlated with agonist efficacy to induce antinociception as measured with irreversible antagonists or using a [ 35 S]GTPγS assay (Mjanger and Yaksh, 1991, Ammer and Schulz, 1993, Traynor and Nahorski, 1995, Goode and Raffa, 1997, McPherson et al, 2010, Madia et al, 2012). It is possible that fentanyl-induced antinociception is differentially mediated through a different MOPr splice variant, Gα protein subtype, or even heterodimers (i.e.…”

Section: Discussionmentioning

confidence: 99%

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

Bobeck

Ingram

Hermes

et al. 2016

Behavioural Brain Research

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Opioids produce antinociception by activation of G protein signaling linked to the mu-opioid receptor (MOPr). However, opioid binding to the MOPr also activates β-arrestin signaling. Opioids such as DAMGO and fentanyl differ in their relative efficacy for activation of these signaling cascades, but the behavioral consequences of this differential signaling are not known. The purpose of this study was to evaluate the behavioral significance of G protein and internalization dependent signaling within ventrolateral periaqueductal gray (vlPAG). Antinociception induced by microinjecting DAMGO into the vlPAG was attenuated by blocking Gαi/o protein signaling with administration of pertussis toxin (PTX), preventing internalization with administration of dynamin dominant-negative inhibitory peptide (dyn-DN) or direct inhibition of ERK1/2 with administration of the MEK inhibitor, U0126. In contrast, the antinociceptive effect of microinjecting fentanyl into the vlPAG was not altered by administration of PTX or U0126, and was enhanced by administration of dyn-DN. Microinjection of DAMGO, but not fentanyl, into the vlPAG induced phosphorylation of ERK1/2, which was blocked by inhibiting receptor internalization with administration of dyn-DN, but not by inhibition of Gαi/o proteins. ERK1/2 inhibition also prevented the development and expression of tolerance to repeated DAMGO microinjections, but had no effect on fentanyl tolerance. These data reveal that ERK1/2 activation following MOPr internalization contributes to the antinociceptive effect of some (e.g., DAMGO), but not all opioids (e.g., fentanyl) despite the known similarities for these agonists to induce β-arrestin recruitment and internalization.

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“…) and the references therein), multiple observations question the primacy and/or exclusivity of the causal association of MOR down‐regulation/uncoupling with narcotic analgesic tolerance: (i) spinal morphine analgesic tolerance occurs in the absence of aggregate MOR G protein uncoupling (Madia et al . ); (ii) the loss of MOR G i /G o coupling is accompanied by the emergence of alternative MOR signaling (Chakrabarti et al . ,b, , ,b, ; Gintzler and Chakrabarti , , ; Chakrabarti and Gintzler ,b, ; Shy et al .…”

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confidence: 99%

Selective up‐regulation of functional mu‐opioid receptor splice variants by chronic opioids

Chakrabarti

Madia

Gintzler

2016

Journal of Neurochemistry

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[35S]GTPγS binding and opioid tolerance and efficacy in mouse spinal cord

Cited by 20 publications

References 44 publications

Mu‐opioid receptor splice variants: sex‐dependent regulation by chronic morphine

Mu‐opioid receptor splice variants: sex‐dependent regulation by chronic morphine

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

Selective up‐regulation of functional mu‐opioid receptor splice variants by chronic opioids

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