Sex chromosome complement affects nociception and analgesia in newborn mice.
In animal studies of nociception, females are often more sensitive to painful stimuli, whereas males are often more sensitive to analgesia induced by mu-agonists. Sex differences are found even at birth, and in adulthood are likely caused, at least in part, by differences in levels of gonadal hormones. In this report, we investigate nociception and analgesia in neonatal mice and assess the contribution of the direct action of sex chromosome genes in hotplate and tail withdrawal tests. We used the 4 core genotypes mouse model, in which gonadal sex is independent of the complement of sex chromosomes (XX vs XY). Mice were tested at baseline and then injected with mu-opioid agonist morphine (10 mg/kg) or with the kappa-opioid agonist U50,488H (U50, 12.5 mg/kg) with or without the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 (0.1 mg/kg). On the day of birth, XX mice showed faster baseline latencies than XY in tail withdrawal, irrespective of their gonadal type. Gonadal males showed greater effects of morphine than gonadal females in the hotplate test, irrespective of their sex chromosome complement. U50 and morphine were effective analgesics in both tests, but MK-801 did not block the U50 effect. The results suggest that sex chromosome complement and gonadal secretions both contribute to sex differences in nociception and analgesia by the day of birth.


CONCLUSIONS
Sex differences in pain may stem not only from the action of gonadal hormones on pain circuits but from the sex-specific action of X and Y genes. Identification of sex chromosome genes causing sex differences could contribute to better pain therapy in females and males.
Gioiosa
Laura
L
Department of Physiological Science and Laboratory of Neuroendocrinology of the Brain Research Institute, University of California, Los Angeles, California 90095-1606, USA.
Chen
Xuqi
X
Watkins
Rebecca
R
Umeda
Elizabeth A
EA
Arnold
Arthur P
AP
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000008:administration & dosage / Q000494:pharmacology; D000698:Analgesia / Q000523:psychology; D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology*; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D016291:Dizocilpine Maleate / Q000008:administration & dosage / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology; D010146:Pain / Q000503:physiopathology / Q000517:prevention & control* / Q000523:psychology; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects; D012727:Sex Characteristics; D012730:Sex Chromosomes / Q000235:genetics*; D019849:Sex Determination Processes; D012737:Sex Factors
D000700:Analgesics; D018712:Analgesics, Non-Narcotic; D000701:Analgesics, Opioid; D018691:Excitatory Amino Acid Antagonists; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D016291:Dizocilpine Maleate; D009020:Morphine