Sex differences in the Nociceptin/Orphanin FQ system in rat spinal cord following chronic morphine treatment

Abstract

Nociceptin/Orphanin FQ (N/OFQ) appears to contribute to the development of morphine tolerance, as blockade of its actions will block or reverse the process. To better understand the contribution of N/OFQ to the development of morphine tolerance, this study examined the effect of chronic morphine treatment on levels of N/OFQ and levels and activity of the N/OFQ peptide (NOP) receptor in spinal cord (SC) from male and female rats. Both male and female Wistar rats showed less responsiveness to morphine after subcutaneous injection of escalating doses of morphine (10, 20, 40, 60 and 80 mg/kg, respectively) twice daily for five consecutive days. Male rats were more tolerant to the antinociceptive actions of morphine than females. The N/OFQ content of SC extracts was higher in females than in males, regardless of treatment; following chronic morphine treatment the difference in N/OFQ levels between males and females was more pronounced. N/OFQ content in cerebrospinal fluid (CSF) was reduced 40% in male and 16% in female rats with chronic morphine exposure, but increased in periaqueductal grey of both sexes. Chronic morphine treatment increased NOP receptor levels 173% in males and 137% in females, while decreasing affinity in both. Chronic morphine increased the efficacy of N/OFQ-stimulated [35S]GTPγS binding to SC membranes from male rats, consistent with increased receptor levels. Taken together, these findings demonstrate sex differences in N/OFQ–NOP receptor expression and NOP receptor activity following chronic morphine treatment. They also suggest interplay between endogenous N/OFQ and chronic morphine treatment that results in nociceptive modulation.

Beneficial effects of co-treatment with dextromethorphan on prenatally methadone-exposed offspring

“…Early studies also showed that intrathecal administration of N/OFQ causes the antinociceptive effect in the monkey and rodents [ 37 , 38 ]. Both of MOR and NOPR could be influenced on expression or affinity by chronic administration of exogenous opioids [ 41 , 42 ]. Several studies have been shown to cross influence another type of opioid receptors when continued activation of one type of opioid receptors.…”

“…For example, chronic treatment with kappa- (κ-) opioid receptor agonist, U50,448H, decreased the expression of both κ- and δ- opioid receptors in the spinal cord and striatum of rats [ 43 ]. It has also been shown that chronic morphine influenced the N/OFQ systems [ 42 , 44 ]. Previous studies also provided evidence that NOPR and MOR not only formed a heterodimer with each other, but also regulated the desensitization function with each other [ 45 - 47 ].…”

Cellular Mechanisms of Nociceptin/Orphanin FQ (N/OFQ) Peptide (NOP) Receptor Regulation and Heterologous Regulation by N/OFQ

“…NOP receptor expression in the brains of MOR knockout mice did not differ from levels in wild-type mice (Slowe et al, 2001), suggesting that activation of MOR by endogenous agonists does not regulate the expression of NOP receptor supraspinally. In contrast, chronic activation of MOR with morphine increased NOP receptor expression in the dorsal spinal cord in mice and rats (Gouarderes et al, 1999;Ueda et al, 2000;Zhang et al, 2012b). Whether chronic morphine treatment also increases NOP receptor expression supraspinally is not yet known.…”

Sex differences in behavioral and brainstem transcriptomic neuroadaptations following neonatal opioid exposure in outbred mice

“…In addition, we identified upregulation of genes involved in nociception, including Pnoc , a gene coding for the precursor protein to nociception. Nociceptin levels in the spinal cord were higher in female rats treated with morphine (Zhang et al, 2012). Together, our findings support the notion that early postnatal exposure to morphine leads to changes in nociceptin signaling, although the potential role in hyperalgesia during opioid withdrawal in neonates is unknown.…”