Regional brain activation in conscious, nonrestrained rats in response to noxious visceral stimulation

Abstract

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 threedimensionally 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.

Translational aspects of rectal evoked potentials: a comparative study in rats and humans

“…Because of anatomical brain differences, comparison of CEPs and the underlying brain activity in rats and humans should be interpreted cautiously. However, functional magnetic resonance imaging studies of both rat and human brains have shown activation of the same brain structures during colorectal distension (36,56). The same structures are likely activated in the present study, and hence the recorded CEPs may reflect comparable activation of the neuroaxis in rats and humans.…”

Cingulate Cortex and Pain Architecture

“…The highest density of cingulate nociceptive neurons is in ACC and they are activated by visceral and cutaneous stimuli (Gao et al, 2006;Sikes et al, 2008) including noxious colorectal distension in unrestrained rats (Wang et al, 2008). When MCC is analyzed, it too has nociceptive responses during noxious cutaneous and colorectal distension (Sikes et al, 2008) and in a pancreatitis model .…”

Experimental Models of Stress and Pain: Do They Help to Develop New Therapies?

“…To capture more objective markers of the animal visceral pain response and to assess possible drug effects on this response, functional brain imaging has been applied to compare the brain response in rodents to that in humans, bypassing the comparison of reflex responses in rodents with subjective verbal symptom reports in humans [89,90] .…”