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

Abstract

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.

Exposure to opiates in female adolescents alters mu opiate receptor expression and increases the rewarding effects of morphine in future offspring

“…There is a growing literature indicating sex-specific expression patterns of opioid receptors as well as endogenous opioid expression, particularly in relation to the differential antinociception response between males and females (Gerald et al, 2008; Kren et al, 2008; Meyer et al, 2000; Wang et al, 2012). For example, it has been shown that there are sex-specific increases in mu opioid receptor expression within the spinal cord in male but not female rats (Verzillo et al, 2014) and the periaqueductal gray region (Loyd et al, 2008). In terms of changes observed in the accumbens, it has been shown that endogenous opioid gene expression is higher in females than males in the nucleus accumbens (Gugusheff et al, 2014).…”

Sex Associated Differential Expressions of the Alternatively Spliced Variants mRNA of OPRM1 in Brain Regions of C57BL/6 Mouse

“…It has been demonstrated that sex differences in the effects of peripheral MOR agonists is partly mediated by sex differences in the changes of MOR expressions [34], tolerance/dependence results from different adaptational strategies (chronic systemic morphine influenced levels of MOR splice variant mRNA) in males and females [35], MOR expression in the PAG was sexually dimorphic contributed to the observed sex differences in morphine potency [36] and testosterone plays a key role in the regulation of MOR under inflammatory conditions and these differences in the antihyperalgesic effects of peripherally administered opioids are mediated by peripheral opioid receptor expression levels partially [37]. Thus, we determined to explore the different effects of μ opioid receptor agonists and aimed to investigate the mRNA expression of MOR variants of different brain regions by SYBR green quantitative PCR (qPCR) in male and female mice and prepared to figure out some certain relationships between MOR variants and these sex-associated reactions.…”

Morphine-induced MOR-1X and ASF/SF2 Expressions Are Independent of Transcriptional Regulation: Implications for MOR-1X Signaling

“…Multiple physiological and environmental stimuli are known to alter constitutive and alternative splicing. Accordingly, chronic use and abuse of opioids, such as methadone and morphine, has been found to alter splicing patterns of the MOR (Vousooghi et al, ; Verzillo et al, ; Xu et al, ). The current study confirms and expands upon these previous findings, as our results demonstrate that morphine treatment significantly increases MOR‐1X mRNA expression in a human cell‐line model of dopaminergic neurons (Fig.…”