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

Chakrabarti, Swapan; Madia, Priyanka A.; Gintzler, Alan R.

doi:10.1111/jnc.13519

Cited by 5 publications

(11 citation statements)

References 84 publications

(174 reference statements)

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“…) strongly suggests that increased association of MOR‐1B2 and MOR‐1C1 with G s α following chronic morphine was functional. This manifestation of increased MOR G s signaling is consistent with our earlier report that chronic morphine treatment can differentially stimulate GTPγS binding (a measure of functional coupling) by MOR‐1B2 and MOR‐1C1, but not MOR‐1 (Chakrabarti et al ).…”

Section: Resultssupporting

confidence: 92%

“…More recently, we reported that mRNA and protein corresponding to both MOR‐1B2 and MOR‐1C1 are up‐regulated in spinal cord (of males) following chronic systemic morphine (Chakrabarti et al ; Verzillo et al ). This study demonstrates that the association of MOR‐1B2 and MOR‐1C1 with G s α is significantly augmented after chronic treatment with morphine.…”

Section: Discussionmentioning

confidence: 99%

“…Cells at their stage of exponential growth rate (70–75% confluency) were used for transfection as mentioned previously (Chakrabarti et al . ). Cells were used between 2 and 14 passages.…”

Section: Methodsmentioning

confidence: 97%

“…Cell culture Chinese Hamster ovary cells [chinese hamster ovary cells (CHO); courtesy of Dr Larry Toll, Florida Atlantic University, Boca Raton, FL, USA] were grown in Dulbecco's Modified Eagle's Medium (DMEM; purchased from Thermo Fisher Scientific; RRID: SCR_ 008452; Waltham, MA, USA) containing high glucose and Lglutamine supplemented with 10% fetal bovine serum and 100 units/ mL penicillin/streptomycin at 37°C in a humidified atmosphere of 90% air/10% CO 2 . Cells at their stage of exponential growth rate (70-75% confluency) were used for transfection as mentioned previously (Chakrabarti et al 2016). Cells were used between 2 and 14 passages.…”

Section: Methodsmentioning

confidence: 99%

“…These functional differences could indicate that particular MOR splice variants differentially adapt to chronic morphine and thus uniquely contribute to the development of opioid tolerance. Recently, we reported that escalating doses of systemic morphine (Cicero and Meyer 1973;Chakrabarti et al 2012), analogous to regimens used clinically for severe intensifying pain, has MOR variant-specific effects, selectively up-regulating MOR-1B2 and MOR-1C1 mRNA (Verzillo et al 2014) as well as the corresponding functionally coupled protein (sufentanil stimulated GTPcS binding) (Chakrabarti et al 2016). The parallel chronic morphineinduced increase in spinal MOR G s signaling (Chakrabarti et al 2012) and MOR-1B2/MOR-1C1 protein (Chakrabarti et al 2016;Verzillo et al 2014) strongly suggests that augmented expression of these variants may contribute to the opioid tolerance-associated shift in MOR signaling from predominantly G i /G o inhibitory to G s stimulatory (Chakrabarti et al 1998a;Gintzler and Chakrabarti 2000;Chakrabarti et al 2005a;Chakrabarti et al 2005b;Chakrabarti and Gintzler 2007).…”

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confidence: 99%

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Phosphorylation of unique C‐terminal sites of the mu‐opioid receptor variants 1B2 and 1C1 influences their Gs association following chronic morphine

Chakrabarti

Liu

Gintzler

2019

Journal of Neurochemistry

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We recently demonstrated in rat spinal cord that a regimen of escalating doses of systemic morphine, analogous to regimens used clinically for chronic pain management, selectively up‐regulates the mu‐opioid receptor (MOR) splice variants MOR‐1B2 and MOR‐1C1 mRNA and functional protein. This study investigated the potential relevance of up‐regulating MOR‐1B2 and MOR‐1C1 to the ability of chronic morphine to shift MOR signaling from predominantly Gi/Go inhibitory to Gs stimulatory. Specifically, we tested the hypotheses that chronic morphine induces phosphorylation of carboxyl terminal sites unique to MOR‐1B2 and MOR‐1C1, and that this phosphorylation is causally related to augmented association of these variants with Gsα. Hypotheses were validated by (i) abolition of the chronic morphine‐induced increment in MOR‐1C1 and MOR‐1B2 association with Gsα by inhibitors of protein kinase A and Casein kinase 2, respectively; (ii) failure of chronic morphine to augment MOR variant Gsα interactions in Chinese hamster ovary cells transiently transfected with either rat MOR‐1C1 or MOR‐1B2 in which targeted protein kinase A and Casein kinase 2 serine phosphorylation sites, respectively, were mutated to alanine; (iii) abrogation of chronic morphine‐induced augmented MOR Gsα association in spinal cord of male rats following intrathecal administration of dicer substrate small interfering RNAs targeting MOR‐1B2/MOR‐1C1 mRNA. The ability of chronic morphine to not only up‐regulate‐specific MOR variants but also their carboxyl terminal phosphorylation and consequent augmented association with Gsα may represent a novel component of opioid tolerance mechanisms, suggesting novel potential targets for tolerance abatement.

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Section: Resultssupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

“…Cells at their stage of exponential growth rate (70–75% confluency) were used for transfection as mentioned previously (Chakrabarti et al . ). Cells were used between 2 and 14 passages.…”

Section: Methodsmentioning

confidence: 97%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Phosphorylation of unique C‐terminal sites of the mu‐opioid receptor variants 1B2 and 1C1 influences their Gs association following chronic morphine

Chakrabarti

Liu

Gintzler

2019

Journal of Neurochemistry

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Relevance of Mu-Opioid Receptor Splice Variants and Plasticity of Their Signaling Sequelae to Opioid Analgesic Tolerance

2020

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Spinal CX3CL1/CX3CR1 May Not Directly Participate in the Development of Morphine Tolerance in Rats

et al. 2017

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CX3CL1 (fractalkine), the sole member of chemokine CX3C family, is implicated in inflammatory and neuropathic pain via activating its receptor CX3CR1 on neural cells in spinal cord. However, it has not been fully elucidated whether CX3CL1 or CX3CR1 contributes to the development of morphine tolerance. In this study, we found that chronic morphine exposure did not alter the expressions of CX3CL1 and CX3CR1 in spinal cord. And neither exogenous CX3CL1 nor CX3CR1 inhibitor could affect the development of morphine tolerance. The cellular localizations of spinal CX3CL1 and CX3CR1 changed from neuron and microglia, respectively, to all the neural cells during the development of morphine tolerance. A microarray profiling revealed that 15 members of chemokine family excluding CX3CL1 and CX3CR1 were up-regulated in morphine-treated rats. Our study provides evidence that spinal CX3CL1 and CX3CR1 may not be involved in the development of morphine tolerance directly.

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

Abstract: We recently reported (Verzillo, et al.

Cited by 5 publications

References 84 publications

Phosphorylation of unique C‐terminal sites of the mu‐opioid receptor variants 1B2 and 1C1 influences their Gs association following chronic morphine

Phosphorylation of unique C‐terminal sites of the mu‐opioid receptor variants 1B2 and 1C1 influences their Gs association following chronic morphine

Relevance of Mu-Opioid Receptor Splice Variants and Plasticity of Their Signaling Sequelae to Opioid Analgesic Tolerance

Spinal CX3CL1/CX3CR1 May Not Directly Participate in the Development of Morphine Tolerance in Rats

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