Regional brain activation in conscious, nonrestrained rats in response to noxious visceral stimulation.
Preclinical drug development for visceral pain has largely relied on quantifying pseudoaffective responses to colorectal distension (CRD) in restrained rodents. However, the predictive value of changes in simple reflex responses in rodents for the complex human pain experience is not known. Male rats were implanted with venous cannulas and with telemetry transmitters for abdominal electromyographic (EMG) recordings. [(14)C]-iodoantipyrine was injected during noxious CRD (60 mmHg) in the awake, nonrestrained animal. Regional cerebral blood flow (rCBF)-related tissue radioactivity was quantified by autoradiography and analyzed in the three-dimensionally reconstructed brain by statistical parametric mapping. 60-mmHg CRD, compared with controls (0 mmHg) evoked significant increases in EMG activity (267+/-24% vs. 103+/-8%), as well as in behavioral pain score (77+/-6% vs. 3+/-3%). CRD elicited significant increases in rCBF as expected in sensory (insula, somatosensory cortex), and limbic and paralimbic regions (including anterior cingulate cortex and amygdala). Significant decreases in rCBF were seen in the thalamus, parabrachial nucleus, periaqueductal gray, hypothalamus and pons. Correlations of rCBF with EMG and with behavioral pain score were noted in the cingulate, insula, lateral amygdala, dorsal striatum, somatosensory and motor regions. Our findings support the validity of measurements of cerebral perfusion during CRD in the freely moving rat as a model of functional brain changes in human visceral pain. However, not all regions demonstrating significant group differences correlated with EMG or behavioral measures. This suggests that functional brain imaging captures more extensive responses of the central nervous system to noxious visceral distension than those identified by traditional measures.
Center for the Neurobiology of Stress, Brain Research Institute, UCLA, Los Angeles, CA, USA Departments of Physiology, Psychiatry and Biobehavioral Sciences, Brain Research Institute, UCLA, Los Angeles, CA, USA VA GLA Healthcare System, Los Angeles, CA, USA Department of Biomedical Engineering, USC, Los Angeles, CA, USA Departments of Psychiatry and the Behavioral Sciences, Cell and Neurobiology, Neurology, USC, Los Angeles, CA, USA Neurology and GI Center of Excellence for Drug Discovery, GlaxoSmithKline, Harlow, UK.
Zhuo
Z
Wang
Sylvie
S
Bradesi
Jean-Michel I
JI
Maarek
Kevin
K
Lee
Wendy J
WJ
Winchester
Emeran A
EA
Mayer
Daniel P
DP
Holschneider
D000818:Animals; D001921:Brain / Q000503:physiopathology*; D003243:Consciousness; D005073:Evoked Potentials, Somatosensory; D006930:Hyperalgesia / Q000209:etiology / Q000503:physiopathology*; D008297:Male; D010812:Physical Stimulation / Q000009:adverse effects / Q000379:methods*; D051381:Rats; D017208:Rats, Wistar; D012149:Restraint, Physical; D014781:Viscera / Q000503:physiopathology*