Gioiosa Laura, Chen Xuqi, Watkins Rebecca, Umeda Elizabeth A, Arnold Arthur P
Department of Physiological Science and Laboratory of Neuroendocrinology of the Brain Research Institute, University of California, Los Angeles, California 90095-1606, USA.
J Pain. 2008 Oct;9(10):962-9. doi: 10.1016/j.jpain.2008.06.001. Epub 2008 Jul 17.
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.
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.
在伤害感受的动物研究中，雌性通常对疼痛刺激更敏感，而雄性通常对μ-激动剂诱导的镇痛更敏感。甚至在出生时就发现了性别差异，在成年期，这种差异至少部分可能是由性腺激素水平的差异引起的。在本报告中，我们研究了新生小鼠的伤害感受和镇痛作用，并在热板和甩尾试验中评估了性染色体基因直接作用的贡献。我们使用了4种核心基因型小鼠模型，其中性腺性别独立于性染色体组成（XX与XY）。在基线时对小鼠进行测试，然后注射μ-阿片激动剂吗啡（10mg/kg）或κ-阿片激动剂U50,488H（U50，12.5mg/kg），有无N-甲基-D-天冬氨酸（NMDA）受体拮抗剂MK-801（0.1mg/kg）。在出生当天，XX小鼠在甩尾试验中的基线潜伏期比XY小鼠快，无论其性腺类型如何。在热板试验中，性腺雄性比性腺雌性对吗啡的反应更大，无论其性染色体组成如何。U50和吗啡在两项试验中都是有效的镇痛药，但MK-801并未阻断U50的作用。结果表明，到出生时，性染色体组成和性腺分泌都对伤害感受和镇痛的性别差异有贡献。
疼痛的性别差异可能不仅源于性腺激素对疼痛回路的作用，还源于X和Y基因的性别特异性作用。鉴定导致性别差异的性染色体基因可能有助于改善对女性和男性的疼痛治疗。
