Sex Differences in Regional Brain Glucose Metabolism Following Opioid Withdrawal and Replacement

Abstract

Methadone and buprenorphine are currently the most common pharmacological treatments for opioid dependence. Interestingly, the clinical response to these drugs appears to be sex specific. That is, females exhibit superior therapeutic efficacy, defined as extended periods of abstinence and longer time to relapse, compared with males. However, the underlying metabolic effects of opioid withdrawal and replacement have not been examined. Therefore, using FDG and microPET, we measured differences in regional brain glucose metabolism in males and females following morphine withdrawal and subsequent methadone or buprenorphine replacement. In both males and females, spontaneous opioid withdrawal altered glucose metabolism in regions associated with reward and drug dependence. Specifically, metabolic increases in the thalamus, as well as metabolic decreases in insular cortex and the periaqueductal gray, were noted. However, compared with males, females exhibited increased metabolism in the preoptic area, primary motor cortex, and the amygdala, and decreased metabolism in the caudate/putamen and medial geniculate nucleus. Methadone and buprenorphine initially abolished these changes uniformly, but subsequently produced their own regional metabolic alterations that varied by treatment and sex. Compared with sex-matched control animals undergoing spontaneous opioid withdrawal, male animals treated with methadone exhibited increased caudate/putamen metabolism, whereas buprenorphine produced increased ventral striatum and motor cortex metabolism in females, and increased ventral striatum and somatosensory cortex metabolism in males. Notably, when treatment effects were compared between sexes, methadone-treated females showed increased cingulate cortex metabolism, whereas buprenorphine-treated females showed decreased metabolism in cingulate cortex and increased metabolism in the globus pallidus. Perhaps the initial similarities in males and females underlie early therapeutic efficacy, whereas these posttreatment sex differences contribute to clinical treatment failure more commonly experienced by the former.

Pain prevalence and treatment in patients with metastatic bone disease

“…In a recent report of health-related quality of life (EQ-5D-5L), it was concluded that men score increased mean values using the visual analog scale (VAS) than women, and that, overall, the VAS mean decreases with age (62). Santoro et al (63) found significant sex differences in regional brain glucose metabolism associated with opioid withdrawal. However, this study was performed in a different setting of patients and with a different treatment goal.…”

Can neuroimaging help combat the opioid epidemic? A systematic review of clinical and pharmacological challenge fMRI studies with recommendations for future research

“…For example, estrogens can diminish opioids' antinociceptive effects [132], there is evidence of interactions and crosstalk between opioid and estrogen receptors [133], and estrogens may impact the antinociceptive and rewarding effects of methadone through effects on methadone metabolism [134]. In addition, recent preclinical work suggests sex-specific effects of acute opioid withdrawal and subsequent opioid replacement (with methadone or buprenorphine) on regional brain metabolism within regions including the anterior cingulate, amygdala and striatum [135,136]. Thus, neuroimaging studies including equal numbers of male and female participants that are specifically powered to detect sex-specific effects are urgently needed in OUD.…”

Sirt3 mediated by lentiviral vector in the periaqueductal gray suppresses morphine withdrawal in rats: A preliminary study

“…In the pilot study, we found that (1) Neuropharmacological studies show that multiple regions of the brain with high opioid receptors, are related to MW or drug abuse in human and animals 13, 15, 32-41 . Anatomical, and neurochemical studies have implicated an important role of the PAG in opioid withdrawal [15][16][17][18][42][43][44] . Distinct PAG columns project to midline and intralaminar thalamic regions 45 .…”

“…locus ceruleus (LC), periaqueductal gray (PAG)) of the brain with high opioid receptors, are related to MW or drug abuse [12][13][14] . Functional and anatomical studies have implicated an important role for the PAG in opioid withdrawal [15][16][17][18] . Sirtuins are protein deacetylases dependent on nicotine adenine dinucleotide (NAD) in organisms ranging from bacteria to humans 19 .…”