Sex differences in functional brain activation during noxious visceral stimulation in rats.
Studies in healthy human subjects and patients with irritable bowel syndrome suggest sex differences in cerebral nociceptive processing. Here we examine sex differences in functional brain activation in the rat during colorectal distention (CRD), a preclinical model of acute visceral pain. [(14)C]-iodoantipyrine was injected intravenously in awake, non-restrained female rats during 60- or 0-mmHg CRD while electromyographic abdominal activity (EMG) and pain behavior were recorded. Regional cerebral blood flow-related tissue radioactivity was analyzed by statistical parametric mapping from autoradiographic images of three-dimensionally reconstructed brains. Sex differences were addressed by comparing the current data with our previously published data collected from male rats. While sex differences in EMG and pain scores were modest, significant differences were noted in functional brain activation. Females showed widespread changes in limbic (amygdala, hypothalamus) and paralimbic structures (ventral striatum, nucleus accumbens, raphe), while males demonstrated broad cortical changes. Sex differences were apparent in the homeostatic afferent network (parabrachial nucleus, thalamus, insular and dorsal anterior cingulate cortices), in an emotional-arousal network (amygdala, locus coeruleus complex), and in cortical areas modulating these networks (prefrontal cortex). Greater activation of the ventromedial prefrontal cortex and broader limbic/paralimbic changes in females suggest greater engagement of affective mechanisms during visceral pain. Greater cortical activation in males is consistent with the concept of greater cortical inhibitory effects on limbic structures in males, which may relate to differences in attentional and cognitive attribution to visceral stimuli. These findings show remarkable similarities to reported sex differences in brain responses to visceral stimuli in humans.
Wang
Zhuo
Z
Center for Neurobiology of Stress; UCLA, Los Angeles, CA, USA.|VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA.|Department of Psychiatry & the Behavioral Sciences, USC, Los Angeles, CA, USA.
Guo
Yumei
Y
Department of Psychiatry & the Behavioral Sciences, USC, Los Angeles, CA, USA.
Bradesi
Sylvie
S
Center for Neurobiology of Stress; UCLA, Los Angeles, CA, USA.|Department of Medicine; UCLA, Los Angeles, CA, USA.|VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA.
Labus
Jennifer S
JS
Center for Neurobiology of Stress; UCLA, Los Angeles, CA, USA.|Department of Psychiatry & Biobehavioral Sciences; UCLA, Los Angeles, CA, USA.|Brain Research Institute, UCLA, Los Angeles, CA, USA.
Maarek
Jean-Michel I
JI
Department of Biomedical Engineering, USC, Los Angeles, CA, USA.
Lee
Kevin
K
Neurology & GI Center of Excellence for Drug Discovery, GlaxoSmithKline, Harlow, UK.
Winchester
Wendy J
WJ
Neurology & GI Center of Excellence for Drug Discovery, GlaxoSmithKline, Harlow, UK.
Mayer
Emeran A
EA
Center for Neurobiology of Stress; UCLA, Los Angeles, CA, USA.|Department of Medicine; UCLA, Los Angeles, CA, USA.|Department of Physiology, UCLA, Los Angeles, CA, USA.|Department of Psychiatry & Biobehavioral Sciences; UCLA, Los Angeles, CA, USA.|Brain Research Institute, UCLA, Los Angeles, CA, USA.|VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA.
Holschneider
Daniel P
DP
VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA.|Department of Biomedical Engineering, USC, Los Angeles, CA, USA.|Department of Psychiatry & the Behavioral Sciences, USC, Los Angeles, CA, USA.|Departments of Neurology, Cell & Neurobiology, USC, Los Angeles, CA, USA.
D000704:Analysis of Variance; D000818:Animals; D000983:Antipyrine / Q000031:analogs & derivatives / Q000378:metabolism; D001345:Autoradiography / Q000379:methods; D001921:Brain / Q000098:blood supply / Q000503:physiopathology*; D001931:Brain Mapping; D002247:Carbon Isotopes / Q000378:metabolism; D004576:Electromyography / Q000379:methods; D030762:Estrous Cycle; D005073:Evoked Potentials, Somatosensory; D005260:Female; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D010100:Oxygen / Q000097:blood; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000502:physiology*; D010812:Physical Stimulation / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D012737:Sex Factors; D018709:Statistics, Nonparametric; D014781:Viscera / Q000503:physiopathology*; D017833:Visceral Afferents / Q000503:physiopathology
D002247:Carbon Isotopes; D010100:Oxygen; D000983:Antipyrine; C008135:iodoantipyrine