Referred Hyperalgesia

As already discussed above, most forms of visceral pain produce an increased tenderness of remote and superficial areas of the body known as referred visceral hyperalgesia (22). The fact that referred hyperalgesia appears to originate from otherwise healthy tissues strongly suggests that their locus of origin is in the CNS rather than in the periphery. The conceptual framework underpinning the central organization of visceral hyperalgesia originates from James MacKenzie, who in his classical 1909 publication, proposed that signals from a diseased viscus arriving in the spinal cord would converge onto somatic pathways and set up an "irritable focus'' in the cord responsible for the enhanced pain sensitivity referred to the somatic area and for the increased motor and autonomic activity characteristic of visceral pain states. This "irritable focus'' in the CNS was the predecessor of what is known today as "central sensitization.''

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Colon distension pressure (mmHg)

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Colon distension pressure (mmHg)

Figure 3 Viscerosomatic convergence in the spinal cord. The figure shows the responses of a viscerosomatic convergent neuron in the spinal cord of the rat to controlled distension of the colon (graph on the left) and the cutaneous receptive field of the neuron (figurines on the right). The responses of the neuron before (control) and after the induction of a colonic inflammation are shown. Note that the inflammation enhances the responses of the neuron to colonic distension and enlarges its cutaneous receptive field. Source: From Ref. 74.

The properties of the "irritable focus'' (central sensitization) have been extensively studied, providing plenty of evidence in support of an enhanced excitability of spinal cord neurons as the mechanism responsible for the manifestation of visceral hyperalgesic states (69,75,76). An injury or inflammation applied to a given viscus will not only result in an enhancement of the responses of the neurons to stimulation of the viscus, but also in an increase in the excitability of the responses mediated by the somatic afferent drives (Fig. 3). This general increase in the excitability of viscerosomatic convergent neurons to all their inputs has been interpreted as the substrate for the generation of referred hyperalgesic states.

A similar mechanism can be hypothesized for referred hyperalgesia in the case of concurrent algogenic conditions from two internal organs sharing at least part of their central sensory projection (viscero-visceral hyperalgesia). Along with viscerosomatic convergence, in fact, experimental evidence exists for viscero-visceral convergence in the CNS, e.g., between the gallbladder and the heart, and between colon and rectum, bladder, vagina and uterine cervix (24,77,78). Thus, increases in the excitability of viscero-viscero-somatic convergent neurons, triggered by the afferent barrage from one visceral organ, could mediate the increased reactivity to impulses from the second visceral organ and the somatic area of referral (43).

As already reported in the section on animal models, referred visceral hyperalgesia can also be detected in animals. For instance, instillation of capsaicin or mustard oil into the colon in the rat evokes not only an immediate, and short-lived, pain reaction of the animal but also leaves an area of referred mechanical hyperalgesia in the abdomen that lasts for more than 24 hours after the initial insult (54) (Fig. 4A). This model has been extensively used to examine the cellular and molecular mechanisms of referred visceral pain and hyperalgesia.

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