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

Abstract

Inconsistencies between species has stunted the progress of developing new analgesics. To increase the success of translating results between species, improved comparable models are required. Twelve rats received rectal balloon distensions on 2 different days separated by 24.3 (SD 24.6) days. Rectal balloon distensions were also performed in 18 humans (mean age: 34 yr; range: 21-56 yr; 12 men) on two separate occasions, separated by 9.3 (SD 5.5) days. In rats, cerebral evoked potentials (CEPs) were recorded by use of implanted skull-electrodes to distension pressure of 80 mmHg. In humans surface electrodes and individualized pressure, corresponding to pain detection threshold, were used. Comparison of morphology was assessed by wavelet analysis. Within-and between-day reproducibility was assessed in terms of latencies, amplitudes, and frequency content. In rats CEPs showed triphasic morphology. No differences in latencies, amplitudes, and power distribution were seen within or between days (all P Ն 0.5). Peak-to-peak amplitude between the first positive and negative potential were the most reproducible characteristic within and between days (evaluated by intraclass correlation coefficients, ICC) (ICC ϭ 0.99 and ICC ϭ 9.98, respectively). In humans CEPs showed a triphasic morphology. No differences in latencies, amplitudes, or power distribution were seen within or between days (all P Ն 0.2). Latency to the second negative potential (ICC ϭ 0.98) and the second positive potential (ICC ϭ 0.95) was the most reproducible characteristic within and between days. A unique and reliable translational platform was established assessing visceral sensitivity in rats and humans, which may improve the translational process of developing new drugs targeting visceral pain.translation; mechanical rectal distension; evoked potentials; reproducibility DEVELOPMENT OF NEW ANALGESICS is very costly. A main contributing factor to this cost is thought to be a result of high attrition rates (27). One reason for these high attrition rates could be inconsistencies between species, resulting in inhibited progress of developing new analgesics. The relatively inadequate predictive value of preclinical animal models used to test pharmacological compounds before using them in human clinical trials increases the demand of objective translational comparable models.Because the underlying pathophysiology remains unknown in many pain and central nervous system disorders, the construct validity of animal models may be limited and unlikely to reflect the clinical picture in humans that they attempt to model. Hence, an increased understanding of the underlying pathophysiological mechanisms will enhance the possibility of creating animal models with better construct validity. However, this remains challenging and an ideal model needs to be accurate, responsive, sensitive to therapy, and better than existing models.An alternative method to increase the predictive values of animal models would be to establish translational comparable experimental methods....

Mechanically evoked cortical potentials: A physiological approach to assessment of anorectal sensory pathways

“…In our experiments, only one peak corresponding to the second (large negative) peak was observed. This may reflect the different stimuli (distention vs. light-touch) or different recording technique (awake animals vs. anaesthetized animals in the current study) (Nissen et al, 2013).…”

“…Rapid rectal balloon distension has previously been used in both animals and humans for evoking cortical potentials (Nissen et al, 2013). However this method has limitations, namely the requirement for costly equipment and a high-pressure system with compliant balloons for accurate stimulation.…”

Pharmacological modulation of colorectal distension evoked potentials in conscious rats

“…Page 3, Nissen TD anaesthetic lidocaine was administered rectally, indicating that interfering with peripheral sensory signaling alters supraspinal responses. Furthermore, we recently showed the translational potential of CEPs induced by CRD, by demonstrating that CEPs with similar morphology can be induced in both rats and humans (6).…”

“…Colorectal distension (CRD) has been used to study experimental visceral sensitivity in both human and animals (1)(2)(3)(4)(5)(6). In human studies, sensory perception is commonly determined by the use of a subjective visual analogue scale (2,7).…”

“…An alternative method to assess the supraspinal response is to record eventrelated cortical evoked potentials (CEPs). In humans, CEPs have been recorded in response to mechanical and electrical stimulation of the rectum to objectively study and assess the brain response in comparison to subjective feedback (6,(18)(19)(20). Rothstein et al showed a correlation between CEP amplitude and stimulation intensities as well as a correlation to the subjective evaluation (2).…”