Studies of the possible mechanisms underlying FBDs have shown that abdominal hypersensi-tivity is an important factor in noncardiac chest pain, functional dyspepsia, and IBS (see Chapters II/3, II/6, II/7, II/9 and II/10). The concept that primary afferents are a relevant target for treating abdominal pain implies that these neurons are sensitized in states of hyper-algesia or undergo other functional changes that are relevant to hypersensitivity. Indeed, most extrinsic afferents innervating the gut have the ability to sensitize in response to a number of proinflammatory mediators and display enhanced excitability following experimentally induced inflammation. The mechanisms whereby hypersensitivity and hyperexcitability of afferent neurons are initiated and maintained are thus of prime pharmacologic interest, if therapeutic options to prevent or reverse sensitization are pursued.
Table 1 Gastrointestinal Hypersensitivity and Primary Afferent Neurons
The pharmacologic treatment of abdominal pain such as that associated with functional bowel disorders (FBDs) is unsatisfactory.
Since the prevalence of FBDs, particularly of functional dyspepsia and irritable bowel syndrome, can be as high as 20%, FBDs represent a significant burden in terms of direct health care and productivity costs.
Emerging evidence indicates that the discomfort and pain in many FBD patients is due to persistent hypersensitivity of primary afferent neurons, which may develop in response to infection, inflammation, or other insults.
This concept identifies sensory neurons as important targets for novel therapies of gastrointestinal hyperalgesia.
Sensory neuron-specific targets can be grouped in three categories: receptors and sensors at the peripheral nerve terminals, ion channels relevant to nerve excitability and conduction, and transmitter receptors.
Particular therapeutic potential is attributed to targets that are selectively expressed by afferent neurons and whose number and function are altered in abdominal hypersensitivity, such as transient receptor potential ion channels of vanilloid type 1 and tetrodotoxin-resistant Na+ channels.
Permanent increases in the sensory gain may be related to changes in the expression of transmitters, receptors, and ion channels, changes in the subunit composition and biophysical properties of receptors and ion channels, or changes in the phenotype, structure, connectivity, and survival of afferent neurons. From a therapeutic point of view, it would be important to know why sensitization is maintained long after the initiating event has gone, because this would help to design strategies to effectively reverse hypersensitivity. A similar issue relates to the question why some patients affected with infectious gastroenteritis develop FBDs whereas others do not. Although the comorbidity of FBDs with depression, anxiety, and related brain disorders (see Chapter II/15) suggests that GI hyperalgesia involves many disturbances in the gut-brain and brain-gut axis, sensory neurons stage as the first element at which to aim novel therapies to control GI pain. In addition, drugs that target nociceptive afferent neurons can be configured such that they do not enter the brain and hence are free of adverse effects on brain functions (1). Sensory neuron-targeting drugs, though, can also have disadvantages if they interfere with important physiologic functions of primary afferents relevant to digestion and with the regulatory roles of peripheral neurons of the enteric and autonomic nervous system. Furthermore, they will be ineffective if hyperalgesia is solely the result of central sensitization processes.
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