title: Spinal and supraspinal N-methyl-D-aspartate and melanocortin-1 receptors contribute to a qualitative sex difference in morphine-induced hyperalgesia.
abstract: Morphine elicits a paradoxical state of increased pain sensitivity, known as morphine-induced hyperalgesia (MIH), which complicates its clinical efficacy. We have previously shown that systemic injections of N-methyl-d-aspartate receptor (NMDAR) and melanocortin-1 receptor (MC1R) antagonists sex-dependently reverse MIH during morphine infusion (40mg/kg/24h) in male and female mice, respectively. This qualitative sex difference is ovarian hormone dependent, as NMDAR antagonists reverse MIH in ovariectomized females but are rendered ineffective following progesterone injection in OVX mice. Here, we utilized intrathecal and intracerebroventricular injection paradigms to assess the contribution of spinal and supraspinal receptors to this sex difference in male and female CD-1 mice. Specifically, we injected NMDAR and MC1R selective antagonists, MK-801 and MSG606 respectively, during morphine infusion. Results illustrated that both spinal and supraspinal MK-801 and MSG606 selectively reversed MIH in males and females, respectively, during morphine infusion. Furthermore, while MK-801 reversed MIH in ovariectomized (OVX) females, MSG606 was most effective in doing so in this same group following an acute subcutaneous progesterone injection. The present studies thus indicate that both spinal and supraspinal NMDARs and MC1Rs underlie the qualitative sex difference observed during morphine infusion in mice, and that the receptors in these loci are also sensitive to sex steroidal modulation.
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, VA Connecticut Healthcare System, 950 Campbell Avenue, West Haven, CT 06516, United States. Electronic address: Caroline.Arout@yale.edu.
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Arout
authors.affiliation: Center for Developmental Neuroscience, The College of Staten Island, City University of New York, Staten Island, NY 10314, United States.
authors.forename: Megan
authors.initials: M
authors.lastname: Caldwell
authors.affiliation: Department of Psychology, Long Island University, Post Campus, Brookville, NY 11548, United States.
authors.forename: Grace
authors.initials: G
authors.lastname: Rossi
authors.affiliation: Center for Developmental Neuroscience, The College of Staten Island, City University of New York, Staten Island, NY 10314, United States; Department of Psychology, The College of Staten Island, City University of New York, Staten Island, NY 10314, United States; Neuropsychology Doctoral Subprogram, The Graduate Center, City University of New York, New York, NY 10016, United States.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Kest
mesh_terms: D000701:Analgesics, Opioid / Q000633:toxicity; D000818:Animals; D001933:Brain Stem / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D005260:Female; D006930:Hyperalgesia / Q000139:chemically induced / Q000473:pathology*; D008297:Male; D051379:Mice; D009020:Morphine / Q000633:toxicity; D009271:Naltrexone / Q000008:administration & dosage; D010052:Ovariectomy; D010147:Pain Measurement; D011374:Progesterone / Q000494:pharmacology; D011372:Progestins / Q000494:pharmacology; D011930:Reaction Time / Q000187:drug effects; D044102:Receptor, Melanocortin, Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012727:Sex Characteristics; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000701:Analgesics, Opioid; D011372:Progestins; D044102:Receptor, Melanocortin, Type 1; D016194:Receptors, N-Methyl-D-Aspartate; D011374:Progesterone; D009271:Naltrexone; D009020:Morphine
keywords: Hyperalgesia; Melanocortin-1 receptor; Morphine; NMDA receptor; Spinal; Supraspinal