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Keywords:

  • cortical evoked potentials;
  • visceral pain;
  • colorectal distension;
  • irritable bowel syndrome

Abstract

  1. Top of page
  2. Abstract
  3. Problem of translation
  4. Primary sensory pathways from the distal gut
  5. Perception of colorectal content
  6. The way forward
  7. Summary and conclusion
  8. Acknowledgments
  9. Funding
  10. Disclosure
  11. Author Contribution
  12. References

Visceral pain is studied at the level of the primary afferent fiber, spinal cord, subcortical, and cortical levels electrophysiologically and using brain imaging, which provides an objective measure of excitation at each level. However, correlation of these with actual perception of pain in conscious animal models has been problematic, and we rely on indirect measures in most preclinical research. The main method is electromyographic recording of abdominal muscle contractions in response to colorectal distension (CRD), which may reflect reflexes set up at several levels of the above pathway. Several experimental treatments for visceral pain have failed in clinical trials, possibly because of failure to translate from preclinical observations on CRD responses in animals to perception of spontaneous events in patients. Therefore, we need more objective outcomes. In this NGM issue, Hultin et al. show feasibility of routine recordings of cortical evoked electrical potentials (CEP) using implanted cranial electrodes in response to graded CRD in rats. CEP comprised three temporal components with latencies of approximately 20–50 ms, 90–180 ms, and 300 ms, which were reproducible and graded in intensity and latency with distension pressure. From this basic study it is clear that colorectal evoked potentials can be recorded reliably in awake rats and may serve as an objective marker for centrally projecting visceral sensory signals in rodents. It remains to be seen how these responses are affected by drugs under development for clinical management of visceral pain, and if there is improved translation.


Problem of translation

  1. Top of page
  2. Abstract
  3. Problem of translation
  4. Primary sensory pathways from the distal gut
  5. Perception of colorectal content
  6. The way forward
  7. Summary and conclusion
  8. Acknowledgments
  9. Funding
  10. Disclosure
  11. Author Contribution
  12. References

An increasingly common question in preclinical neurogastroenterology research nowadays is ‘why don’t drugs effective in reducing visceral pain markers in animal models work in the clinic?’ The answer may lie in species differences, in choice of experimental stimuli, or in interpretation of outcomes, among other possibilities, but we do not know which or all of these areas will provide solutions. Some things are certain: firstly, that we lack animal models that reflect precisely the true pathology of visceral pain syndromes in humans; secondly, that we cannot assess pain in animal models using anything other than surrogate markers; thirdly, that we do not know how peripheral visceral pain pathways work in humans. Improvements are being made in the first and third of these areas of need, including use of different pathogens and combination of disease modeling strategies, direct assessment of sensory fiber activity in human tissue and brain imaging. The second area, that of development of markers for pain, has stagnated somewhat in recent years. The main method used conventionally is electromyographic recording of abdominal muscle contractions in response to colorectal distension (CRD), also known as the visceromotor response (VMR). This may reflect reflexes set up at various levels of the visceral pain pathway, but maybe not what reaches cortical level. Therefore, there is a need for discussion of more objective outcomes in this type of preclinical investigation, but first a brief overview of the visceral pain pathway.

Primary sensory pathways from the distal gut

  1. Top of page
  2. Abstract
  3. Problem of translation
  4. Primary sensory pathways from the distal gut
  5. Perception of colorectal content
  6. The way forward
  7. Summary and conclusion
  8. Acknowledgments
  9. Funding
  10. Disclosure
  11. Author Contribution
  12. References

For a detailed review, see recent articles by my group1,2 and others.3,4 Briefly, for the purposes of this account, the colon and rectum are endowed with several classes of afferent fibers which are specialized to respond to presumably noxious or innocuous stimuli or both. These include tactile mucosal stimulation (innocuous), chemical mediators (both), distension or contraction at physiological levels (innocuous), and distension or contraction at noxious levels. The seven types so far described in the mouse are mucosal, muscular–mucosal, muscular, serosal, mesenteric, mechanically insensitive, and silent, although there is difference in definitions between reports, and some classify afferents only according to distension responses into high and low threshold categories. As far as we know, all these classes of afferent fibers project into the dorsal horn of the spinal cord. According to in vitro mouse data from my group, serosal and mesenteric afferents have thresholds to CRD of 40–50 mmHg.5,6In vivo rat data from Sengupta and colleagues show a population of high threshold afferents with similar thresholds.7 This level correlates with thresholds for pain in human volunteers, which are reduced in patients with irritable bowel syndrome.8 Correspondingly, we have suggested that these afferents are specific nociceptors. They travel mainly in the splanchnic nerves from throughout the distal colon to the thoracolumbar spinal cord, but a significant proportion reach the lumbosacral spinal cord from the rectum via the pelvic nerves. In addition to these ‘specific nociceptors’, both muscular and muscular-mucosal afferents respond to distension, but at low thresholds. However, they continue to increase their responses with increasing distension into the noxious range, so they are wide dynamic range afferents, and exist mainly in the pelvic innervation distal to the distal colon. They presumably provide graded sensations ranging from gas to urge, discomfort and ultimately pain, depending on convergent information received simultaneously by the central nervous system from other afferent classes about the consistency, viscosity, and distensibility of intraluminal contents. Presumably the main nerve pathway activated will provide information as to the proximo-distal localization of the perceived event.

Perception of colorectal content

  1. Top of page
  2. Abstract
  3. Problem of translation
  4. Primary sensory pathways from the distal gut
  5. Perception of colorectal content
  6. The way forward
  7. Summary and conclusion
  8. Acknowledgments
  9. Funding
  10. Disclosure
  11. Author Contribution
  12. References

From the dorsal horn of the thoracolumbar and lumbosacral spinal cord, neurons are activated which project directly to various regions of the brain. Firstly, however, these neurons are subject to powerful modulation by local and descending interneurons, which may reduce or increase the centrally directed signal.9 The dorsal horn is therefore a critical point in the central processing pathway of colorectal sensory information. There are a number of viscero-visceral and viscero-somatic reflexes to similar or different parts of the body that can be set up at the level of the dorsal horn, but it is difficult to say which elements of these reflexes depend on modulation, permissive control, or direct participation of supraspinal and thalamocortical regions, and therefore which of them reflect the occurrence of perception of pain. In human brain imaging studies, areas of the central nervous system most closely associated with perception of pain are the anterior cingulate cortex and the anterior insula, which reflect the affective and sensory aspects of pain, respectively,8 but it is not yet known how subcortical and spinal activation reflects pain perception. Therefore, it is unclear whether recording reflexes such as the VMR is useful in predicting pain perception. A landmark study in this respect was that by Lindström et al.,10 which showed that a 5HT1A antagonist was able to reduce the VMR in conscious rats, but did not affect the increase in blood pressure after CRD (measured using telemetric manometry). Coincidentally this drug was totally without effect in human clinical studies of visceral pain, suggesting that cardiovascular and VMR are mediated at different levels of the central nervous system, and that cardiovascular responses may correlate better with pain in the clinic.

The way forward

  1. Top of page
  2. Abstract
  3. Problem of translation
  4. Primary sensory pathways from the distal gut
  5. Perception of colorectal content
  6. The way forward
  7. Summary and conclusion
  8. Acknowledgments
  9. Funding
  10. Disclosure
  11. Author Contribution
  12. References

In this issue of Neurogastroenterology and Motility, Hultin et al.11 show that it is feasible in routine preclinical studies of visceral sensation to record cortical evoked electrical potentials using implanted cranial electrodes in response to graded CRD in rats. This is a good example of reverse translation, as many such studies have been performed in humans, although few have been able to use distension as a stimulus to mimic the natural events in the colon. The reason for this is the short latency of evoked potentials after the stimulus of a few tens of milliseconds, which is clearly evident with electrical stimulation of afferent pathways.12 Thus, CRD is of limited value, as it may take several seconds using a barostat in humans to reach pain threshold at around 40 mmHg. However, in animal models this may be achieved with smaller volumes, and therefore much more rapidly. Hultin et al.11 have refined the evoked potential method so that they consistently record cortical evoked potentials using implanted cranial electrodes in rats. The implantation surgery is relatively straightforward and animals are comfortable with the electrode and lead assembly for many weeks postoperatively. Similar waveforms of evoked potential were seen to those in humans and comprised three temporal components consisting of five prominent negative and positive peaks. Peak latencies of these three components were approximately 20–50 ms, 90–180 ms, and 300 ms. These responses were reproducible on repeated CRD and graded in intensity with distension pressure. As seen in human studies, latency was correspondingly shorter with increasing distension pressure. The onset of the distension was remarkably fast, and unlikely to reflect physiological increases in intraluminal pressure. However, this is a necessary sacrifice in the establishment of an objective marker for cortical representation of visceral sensation in animals. It could be argued that with rapid onset distension it is more likely to activate nociceptive pathways at lower intensities, so this should be taken into account in future pharmacological studies. Evoked potentials after electrical stimulation of the colorectum showed similar topography and latencies as the mechanical evoked potentials, also with intensity dependence, which is an important validation of the method in comparison with conventional methodology. Another important validation was the use of local anesthesia to show that responses were indeed evoked from the colon and rectum rather than surrounding organs that may have been displaced by the stimulus. Concerning the afferent pathway that was activated in this study, the positioning of the stimulating balloon is of major relevance. It is clear from a number of studies that the pathway of afferent information from the distal colon is distinct from that from the rectum.13 It is also clear that different sensations can be evoked from these two locations in humans and they may play different roles in IBS.14 Therefore, it would be very informative to have data on potentials evoked specifically from each region, to know how sensitive each is to low and high levels of distension, given the facts presented earlier on the different types of afferent fiber following specific pathways from specific locations. It is hoped that this article will stimulate research on the meaning of colonic and rectal evoked potentials in terms of pain or other sensations in humans and animal models.

Summary and conclusion

  1. Top of page
  2. Abstract
  3. Problem of translation
  4. Primary sensory pathways from the distal gut
  5. Perception of colorectal content
  6. The way forward
  7. Summary and conclusion
  8. Acknowledgments
  9. Funding
  10. Disclosure
  11. Author Contribution
  12. References

From the basic study by Hultin et al. it is clear that colorectal evoked potentials can be recorded reliably in awake rats and may serve as an objective marker for centrally projecting visceral sensory signals in rodents. It remains to be seen how these responses are affected by drugs under development for clinical management of visceral pain, and if there is improved translation. In particular it is of interest to see how evoked potentials may correlate with VMR or cardiovascular responses to noxious and innocuous stimuli. IBS presenting clinically is defined as having a major component of pain, but other features including bloating and urge are perhaps just as relevant. Whether we will ever have preclinical readouts of these symptoms is dependent on refinement of approaches such as those developed by Hultin et al., and in turn whether we will ever have a preclinical model of IBS.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Problem of translation
  4. Primary sensory pathways from the distal gut
  5. Perception of colorectal content
  6. The way forward
  7. Summary and conclusion
  8. Acknowledgments
  9. Funding
  10. Disclosure
  11. Author Contribution
  12. References

Ashley Blackshaw is Professor of Enteric Neuroscience at Barts and the London School of Medicine and Dentistry, supported by a Wellcome Trust University Award.

References

  1. Top of page
  2. Abstract
  3. Problem of translation
  4. Primary sensory pathways from the distal gut
  5. Perception of colorectal content
  6. The way forward
  7. Summary and conclusion
  8. Acknowledgments
  9. Funding
  10. Disclosure
  11. Author Contribution
  12. References
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