Chapter 11 - Responses of afferent neurons to the contents of the digestive tract, and their relation to endocrine and immune responses

Complex regional pain syndrome (CRPS), formerly known as reflex sympathetic dystrophy (RSD), is a difficult to treat condition characterized by debilitating pain and limitations in functional ability. Neuromodulation, in the form of spinal cord stimulation (SCS) and peripheral nerve stimulation (PNS), have been traditionally used as a treatment for CRPS with variable success.

This chart review describes the use of implantable PNS systems in the treatment of CRPS of the upper and lower extremities spanning nearly three decades.

A retrospective chart review was performed on 240 patients with PNS implanted between 1990 and 2017 at our institution. Of these, 165 patients were identified who had PNS systems implanted for a diagnosis of CRPS. Patient profile, including baseline characteristics, comorbidities, past/current interventions/medications and targeted nerves, was descriptively summarized through standard summary statistics. Patients' pain scores and opioid consumptions at baseline (preimplant), 1 month, 6 months, and 12 months were collected and compared. Device revisions and explants were summarized, and patient functional outcomes were described.

Pain scores at baseline and at 12-month follow-up were decreased from a mean of 7.4 ± 1.6 to 5.5 ± 2.4 and estimated to be 1.87 (95% CI: [1.29, 2.46], paired t-test p-value <0.001) lower at 12 months. At baseline, 62% of patients were on chronic opioid therapy, compared with 41% at 12 months. Of 126 patients who reported changes in functional status, 64 (51%) reported improvement, 27 (21%) reported worsening, and 35 (28%) did not report any meaningful change. Excluding end-of-life battery replacements, surgical revision occurred in 56 (34%) of patients. Thirteen patients (8%) underwent implantation of a second PNS because of symptomatic expansion outside of the original painful region. Device explant was performed in 32 (19%) of patients. Median length of follow-up was 74 [14, 147] months. Of the 36 patients who continue to follow-up at our institution, 29 (81%) continue to use their PNS.

We can conclude that PNS is a useful modality to improve function and reduce long-term pain in selected patients suffering from CRPS type I and type II.

Vagal afferents innervate a diverse range of structures of the thoracic and abdominal viscera. While a proportion of these afferents function as mechanoreceptors and respond to changes in intramural tension within the structures that they innervate, many also sense a broad range of chemical substances ranging from peptides, sugars and lipids present in the intraluminal contents of the gastrointestinal tract, as well as tissue prostanoids, cytokines and monoamines in the cardiopulmonary circulation. This review examines the effects of chemical stimulation of vagal afferents on circulatory and sympathetic vasomotor function. Notably, the von Bezold–Jarisch reflex is a cardiorespiratory reflex produced by chemical activation of cardiopulmonary vagal afferents. Classical stimulants of the von Bezold–Jarisch reflex include the Veratrum alkaloids and 5-HT₃ receptor agonists. Atrial natriuretic peptides are agents which also produce a von Bezold–Jarisch reflex-like response or a sensitisation of this reflex via an action on vagal afferents. Cholecystokinin (CCK) activates abdominal visceral vagal afferents, which apart from a clear role in mediation of satiety, also produces selective sympathetic vasomotor inhibition probably by inhibition of sub-groups of presympathetic vasomotor neurons of the rostral ventrolateral medulla. These actions of CCK may constitute a novel gastrointestinal-cardiovascular reflex. The afferent vagus transmits a diverse array of signals to the central nervous system, influencing sympathetic vasomotor and cardiomotor function, gastrointestinal function, neuroimmune function and endocrine function.

Diseases in fish are serious problems for the development of aquaculture. The outbreak of fish disease is largely dependent on environmental and endogenous factors resulting in opportunistic infection. Recent studies, particularly on stress response, have revealed that bidirectional communication between the endocrine and immune systems via hormones and cytokines exists at the level of teleost fish. Recently information on such messengers and receptors has accumulated in fish research particularly at the molecular level. Furthermore, it has become apparent in fish that cells of the immune system produce or express hormones and their receptors and vice versa to exchange information between the two systems. This review summarizes and updates the knowledge on endocrine-immune interactions in fish with special emphasis on the roles of such mediators or receptors for their interactions.

An intricate surveillance network consisting of enteroendocrine cells, immune cells and sensory nerve fibres monitors the luminal and interstitial environment in the alimentary canal. Functional bowel disorders are characterized by persistent alterations in digestive regulation and gastrointestinal discomfort and pain. Visceral hyperalgesia may arise from an exaggerated sensitivity of peripheral afferent nerve fibres and/or a distorted processing and representation of gut signals in the brain. Novel strategies to treat these sensory bowel disorders are therefore targeted at primary afferent nerve fibres. These neurons express a number of molecular traits including transmitters, receptors and ion channels that are specific to them and whose number and/or behaviour may be altered in chronic visceral pain. The targets under consideration comprise vanilloid receptor ion channels, acid-sensing ion channels, sensory neuron-specific Na⁺ channels, P2X₃ purinoceptors, 5-hydroxytryptamine (5-HT), 5-HT₃ and 5-HT₄ receptors, cholecystokinin CCK₁ receptors, bradykinin and prostaglandin receptors, glutamate receptors, tachykinin and calcitonin gene-related peptide receptors as well as peripheral opioid and cannabinoid receptors. The utility of sensory neuron-targeting drugs in functional bowel disorders will critically depend on the compounds' selectivity of action for afferent versus enteric or central neurons.