Sex-based differences in gastrointestinal pain
ABSTRACT Recent interest has focused on sex-related differences in irritable bowel syndrome (IBS) physiology and treatment responsiveness to novel pharmacologic therapies. Similar to a variety of other chronic pain conditions and certain affective disorders, IBS is more prevalent amongst women, both in population-based studies as well as in clinic-based surveys. Non-painful gastrointestinal symptoms, constipation and somatic discomfort are more commonly reported by female IBS patients. While perceptual differences to rectosigmoid stimulation are only observed following repeated noxious stimulation of the gut, sex-related differences in certain sympathetic nervous system (SNS) responses to rectosigmoid stimulation are consistently seen. Consistent with experimental findings in animals, current evidence is consistent with a pathophysiological model which emphasizes sex-related differences in autonomic and antinociceptive responses to certain visceral stimuli.
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ABSTRACT: Differences in brain responses to aversive visceral stimuli may underlie previously reported sex differences in symptoms as well as perceptual and emotional responses to such stimuli in patients with irritable bowel syndrome (IBS). The goal of the current study was to identify brain networks activated by expected and delivered aversive visceral stimuli in male and female patients with chronic abdominal pain, and to test for sex differences in the effective connectivity of the circuitry comprising these networks. Network analysis was applied to assess the brain response of 46 IBS patients (22 men and 24 women) recorded using [15O] water positron emission tomography during rest/baseline and expected and delivered aversive rectal distension. Functional connectivity results from partial least squares analyses provided support for the hypothesized involvement of 3 networks corresponding to: 1) visceral afferent information processing (thalamus, insula and dorsal anterior cingulate cortex, orbital frontal cortex), 2) emotional-arousal (amygdala, rostral and subgenual cingulate regions, and locus coeruleus complex) and 3) cortical modulation (frontal and parietal cortices). Effective connectivity results obtained via structural equation modeling indicated that sex-related differences in brain response are largely due to alterations in the effective connectivity of emotional-arousal circuitry rather than visceral afferent processing circuits. Sex differences in the cortico-limbic circuitry involved in emotional-arousal, pain facilitation and autonomic responses may underlie the observed differences in symptoms, and in perceptual and emotional responses to aversive visceral stimuli.NeuroImage 08/2008; 41(3):1032-43. DOI:10.1016/j.neuroimage.2008.03.009 · 6.13 Impact Factor
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ABSTRACT: Pain symptoms in several chronic pain disorders in women, including irritable bowel syndrome, fluctuate with the menstrual cycle suggesting a gonadal hormone component. In female rats, estrogens modulate visceral sensitivity although the underlying mechanism(s) are unknown. In the present study the effects of 17-beta estradiol on N-methyl-D-aspartate (NMDA) receptor signaling of colorectal nociceptive processing in the spinal cord were examined. Estrogen receptor alpha and the NR1 subunit of the NMDA receptor are co-expressed in dorsal horn neurons, supporting a direct action of estradiol on NMDA receptors. Intrathecal administration of the NMDA receptor antagonist D(-)-2-amino-5-phosphonopentanoic acid (APV) dose-dependently attenuated the visceromotor response with greater potency in ovariectomized (OVx) rats compared to OVx with estradiol replacement (E2) rats. Estradiol significantly increased protein expression of NR1 in the lumbosacral spinal cord compared to OVx rats. Colorectal distention significantly increased phosphorylation of NR1ser-897, a PKA phosphorylation site on the NR1 subunit in E2, but not OVx rats. Intrathecal administration of a PKA inhibitor significantly attenuated the visceromotor response, decreased NR1 phosphorylation and increased the potency of APV to attenuate the visceromotor response compared to vehicle-treated E2 rats. These data suggest that estradiol increases spinal processing of visceral nociception by increasing NMDA receptor NR1 subunit expression and increasing site-specific receptor phosphorylation on the NR1 subunit contributing to an increase in NMDA receptor activity.Pain 08/2008; 137(3):540-9. DOI:10.1016/j.pain.2007.10.017 · 5.84 Impact Factor
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ABSTRACT: We tested the role of sex chromosome complement and gonadal hormones in sex differences in several different paradigms measuring nociception and opioid analgesia using "four core genotypes" C57BL/6J mice. The genotypes include XX and XY gonadal males, and XX and XY gonadal females. Adult mice were gonadectomized and tested 3-4 weeks later, so that differences between sexes (mice with testes vs. ovaries) were attributable mainly to organizational effects of gonadal hormones, whereas differences between XX and XY mice were attributable to their complement of sex chromosomes. In Experiment 1 (hotplate test of acute morphine analgesia), XX mice of both gonadal sexes had significantly shorter hotplate baseline latencies prior to morphine than XY mice. In Experiment 2 (test of development of tolerance to morphine), mice were injected twice daily with 10 mg/kg morphine or saline for 6 days. Saline or the competitive NMDA antagonist CPP (3-(2-carboxypiperazin-4yl) propyl-1-phosphonic acid) (10 mg/kg) was co-injected. On day 7, mice were tested for hotplate latencies before and after administration of a challenge dose of morphine (10 mg/kg). XX mice showed shorter hotplate latencies than XY mice at baseline, and the XX-XY difference was greater following morphine. In Experiment 3, mice were injected with morphine (10 mg/kg) or saline, 15 min before intraplantar injection of formalin (5%/25 microl). XX mice licked their hindpaw more than XY mice within 5 min of formalin injection. The results indicate that X- or Y-linked genes have direct effects, not mediated by gonadal secretions, on sex differences in two different types of acute nociception.Hormones and Behavior 02/2008; 53(1):124-30. DOI:10.1016/j.yhbeh.2007.09.003 · 4.51 Impact Factor