Sex differences in functional brain activation during noxious visceral stimulation in rats
Received 19 December 2008; received in revised form 3 May 2009; accepted 27 May 2009. published online 29 June 2009.
Abstract
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. [14C]-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.
aCenter for Neurobiology of Stress, UCLA, Los Angeles, CA, USA
bDepartment of Medicine, UCLA, Los Angeles, CA, USA
cDepartment of Physiology, UCLA, Los Angeles, CA, USA
dDepartment of Psychiatry & Biobehavioral Sciences, UCLA, Los Angeles, CA, USA
eBrain Research Institute, UCLA, Los Angeles, CA, USA
fVA Greater Los Angeles Healthcare System, Los Angeles, CA, USA
gDepartment of Biomedical Engineering, USC, Los Angeles, CA, USA
hDepartment of Psychiatry & the Behavioral Sciences, USC, Los Angeles, CA, USA
iDepartments of Neurology, Cell & Neurobiology, USC, Los Angeles, CA, USA
jNeurology & GI Center of Excellence for Drug Discovery, GlaxoSmithKline, Harlow, UK
Corresponding author. Address: Dept. of Psychiatry and the Behavioral Sciences, Keck School of Medicine, University of Southern California, 1333 San Pablo St., BMT 403, Los Angeles, CA 90089-9112, USA. Tel.: +1 323 442 1536; fax: +1 323 442 1587.
ABSTRACT