Central neural mechanisms mediating human visceral hypersensitivity

Although visceral hypersensitivity is thought to be important in generating symptoms in functional gastrointestinal disorders, the neural mechanisms involved are poorly understood. We recently showed that central sensitization (hyperexcitability of spinal cord sensory neurones) may play an important role. In this study, we demonstrate that after a 30-min infusion of 0.15 M HCl acid into the healthy human distal esophagus, we see a reduction in the pain threshold to electrical stimulation of the non-acid-exposed proximal esophagus (9.6 +/- 2.4 mA) and a concurrent reduction in the latency of the N1 and P2 components of the esophageal evoked potentials (EEP) from this region (10.4 +/- 2.3 and 15.8 +/- 5.3 ms, respectively). This reduced EEP latency indicates a central increase in afferent pathway velocity and therefore suggests that hyperexcitability within the central visceral pain pathway contributes to the hypersensitivity within the proximal, non-acid-exposed esophagus (secondary hyperalgesia/allodynia). These findings provide the first electrophysiological evidence that central sensitization contributes to human visceral hypersensitivity.     

Central mechanisms of pathological pain

Chronic pain is a major challenge to clinical practice and basic science. The peripheral and central neural networks that mediate nociception show extensive plasticity in pathological disease states. Disease-induced plasticity can occur at both structural and functional levels and is manifest as changes in individual molecules, synapses, cellular function and network activity. Recent work has yielded a better understanding of communication within the neural matrix of physiological pain and has also brought important advances in concepts of injury-induced hyperalgesia and tactile allodynia and how these might contribute to the complex, multidimensional state of chronic pain. This review focuses on the molecular determinants of network plasticity in the central nervous system (CNS) and discusses their relevance to the development of new therapeutic approaches.     

Pathobiology of visceral pain: molecular mechanisms and therapeutic implications V. Central nervous system processing of somatic and visceral sensory signals

Somatic and visceral sensation, including pain perception, can be studied noninvasively in humans with functional brain imaging techniques. Positron emission tomography and functional magnetic resonance imaging have identified a series of cerebral regions involved in the processing of somatic pain, including the anterior cingulate, insular, prefrontal, inferior parietal, primary and secondary somatosensory, and primary motor and premotor cortices, the thalamus, hypothalamus, brain stem, and cerebellum. Experimental evidence supports possible specific roles for individual structures in processing the various dimensions of pain, such as encoding of affect in the anterior cingulate cortex. Visceral sensation has been examined in the setting of myocardial ischemia, distension of hollow viscera, and esophageal acidification. Although knowledge regarding somatic sensation is more extensive than the information available for visceral sensation, important similarities have emerged between cerebral representations of somatic and visceral pain.     

Central mechanisms of pain modulation.

Bulbospinal serotonergic neurons and two physiological classes of bulbospinal nonserotonergic cells interact to modulate pain transmission. Recent studies have begun to elaborate targets of descending pain modulation other than the well-studied flexion withdrawal pathways. Site-specific, naloxone-sensitive placebo analgesia, which is hard to reconcile with current models of descending pain modulation, presents an exciting challenge to the field.     

Central nervous system mechanisms for pain modulation

Although a great deal has been learned about the neural basis for stimulation-produced analgesia, it is evident that the 'analgesia systems' are much more complex than was initially thought. Part of the complexity derives from the fact that a number of different pathways, using several different neurotransmitters, can affect nociceptive transmission. Further complexity stems from evidence that nociceptive transmission can be modulated both at a spinal cord level and at higher levels of the nociceptive projection system, such as the thalamus. Hopefully, a greater understanding of the 'analgesia systems' will lead to explanations for a number of puzzling aspects of pain and perhaps to improved therapy.     

Pathobiology of visceral pain: molecular mechanisms and therapeutic implications IV. Visceral afferent contributions to the pathobiology of visceral pain

Functional bowel and other visceral disorders exhibit multiple characteristics that suggest the presence of visceral hyperalgesia. The discomfort, pain, and altered sensations (e.g., to intraluminal contents) that define the hyperalgesia typically arise in the absence of tissue insult or inflammation. Visceral hyperalgesia thus differs from somatic hyperalgesia, which is commonly associated with tissue injury and inflammation. Hyperalgesia could develop and be maintained by either peripheral or central mechanisms; the altered sensations associated with functional visceral disorders are contributed to by both peripheral and central mechanisms. The relative contributions of peripheral and central mechanisms are not well understood, and the focus in this Themes article is on potential peripheral contributions: sensitization of visceral receptors, nerve injury, and ion channels.     

Central representation of visceral function

Recent studies of the visceral sensory system, using both electrophysiological and neuroanatomical methods, indicate that there is representation of multiple visceral modalities at all levels of the central nervous system. In the nucleus of the solitary tract gustatory afferents are represented rostrally, and general visceral afferents caudally. At the pontine relay, the parabrachial nucleus, the gustatory afferents are represented medially, and the general visceral afferents laterally. Although the evidence for anatomical separation of visceral projections is incomplete for the hypothalamus and amygdala, the visceral sensory thalamus and cortex are viscerotopically organized. The results indicate that the ascending visceral sensory system is viscerotopically organized at all levels of the brain, and that this information is important for the integration of autonomic responses at all levels of the neuroaxis.     

Central neural mechanisms that interrelate sensory and affective dimensions of pain

The perception of pain is highly complex, and requires neural integration from a variety of routes. Spinal pathways to the amygdala, hypothalamus, reticular formation, medial thalamic nuclei, and limbic cortical structures transmit information involved arousal, bodily regulation, and emotional responses. Other, albeit indirect, pathways can carry signals to these same structures, for example, from spinal pathways to somatosensory thalamic and cortical areas, and from these to cortical limbic structures. Indirect cortico-limbic pathways integrate nociception with information about the status of the body and indirect routes must culminate in the prioritization of emotions and responses to pain.     

Purinergic mechanosensory transduction and visceral pain

Background

Little is known about whether peripheral nerve injury during the early postnatal period modulates synaptic efficacy in the immature superficial dorsal horn (SDH) of the spinal cord, or whether the neonatal SDH network is sensitive to the proinflammatory cytokine TNFα under neuropathic conditions. Thus we examined the effects of TNFα on synaptic transmission and intrinsic membrane excitability in developing rat SDH neurons in the absence or presence of sciatic nerve damage.

Results

The spared nerve injury (SNI) model of peripheral neuropathy at postnatal day (P)6 failed to significantly alter miniature excitatory (mEPSCs) or inhibitory (mIPSCs) postsynaptic currents in SDH neurons at P9-11. However, SNI did alter the sensitivity of excitatory synapses in the immature SDH to TNFα. While TNFα failed to influence mEPSCs or mIPSCs in slices from sham-operated controls, it significantly increased mEPSC frequency and amplitude following SNI without modulating synaptic inhibition onto the same neurons. This was accompanied by a significant decrease in the paired-pulse ratio of evoked EPSCs, suggesting TNFα increases the probability of glutamate release in the SDH under neuropathic conditions. Similarly, while SNI alone did not alter action potential (AP) threshold or rheobase in SDH neurons at this age, TNFα significantly decreased AP threshold and rheobase in the SNI group but not in sham-operated littermates. However, unlike the adult, the expression of TNFα in the immature dorsal horn was not significantly elevated during the first week following the SNI.

Conclusion

Developing SDH neurons become susceptible to regulation by TNFα following peripheral nerve injury in the neonate. This may include both a greater efficacy of glutamatergic synapses as well as an increase in the intrinsic excitability of immature dorsal horn neurons. However, neonatal sciatic nerve damage alone did not significantly modulate synaptic transmission or neuronal excitability in the SDH, which could reflect a relatively weak expression of TNFα in the injured spinal cord at early ages. The above data suggest that although the sensitivity of the SDH network to proinflammatory cytokines after nerve injury is present from the first days of life, the profile of spinal cytokine expression under neuropathic conditions may be highly age-dependent.     

Cerebellar control of visceral responses-possible mechanisms involved

It seems reasonable to assume that cerebellar autonomic control operates according to similar principles as those utilized in the somatomotor coordination. The unique and very uniform neuronal architecture throughout the cerebellum speaks in favour of such a view.     

Subdiaphragmatic vagal afferent nerves modulate visceral pain

Activation of the vagal afferents by noxious gastrointestinal stimuli suggests that vagal afferents may play a complex role in visceral pain processes. The contribution of the vagus nerve to visceral pain remains unresolved. Previous studies reported that patients following chronic vagotomy have lower pain thresholds. The patient with irritable bowel syndrome has been shown alteration of vagal function. We hypothesize that vagal afferent nerves modulate visceral pain. Visceromotor responses (VMR) to graded colorectal distension (CRD) were recorded from the abdominal muscles in conscious rats. Chronic subdiaphragmatic vagus nerve sections induced 470, 106, 51, and 54% increases in VMR to CRD at 20, 40, 60 and 80 mmHg, respectively. Similarly, at light level of anesthesia, topical application of lidocaine to the subdiaphragmatic vagus nerve in rats increased VMR to CRD. Vagal afferent neuronal responses to low or high-intensity electrical vagal stimulation (EVS) of vagal afferent Adelta or C fibers were distinguished by calculating their conduction velocity. Low-intensity EVS of Adelta fibers (40 microA, 20 Hz, 0.5 ms for 30 s) reduced VMR to CRD at 40, 60, and 80 mmHg by 41, 52, and 58%, respectively. In contrast, high-intensity EVS of C fibers (400 microA, 1 Hz, 0.5 ms for 30 s) had no effect on VMR to CRD. In conclusion, we demonstrated that vagal afferent nerves modulate visceral pain. Low-intensity EVS that activates vagal afferent Adelta fibers reduced visceral pain. Thus EVS may potentially have a role in the treatment of chronic visceral pain.     

Central mechanisms of vascular headaches

The intracranial blood vessels supplying the dura and brain are innervated by sensory afferents from the trigeminal nerve. These fibers are believed to be responsible for conveying the pain associated with vascular head pain such as migraines. This paper reviews recently published data describing the existence of neurons within the cat trigeminal nucleus and thalamus that respond to electrical stimulation of the middle meningeal artery and superior sagittal sinus. Almost all of these neurons receive convergent input from the facial skin and most of the receptive fields include the periorbital region. On the basis of their cutaneous inputs, most of the neurons are classified as nociceptive. The characteristics of these cerebrovascular-activated neurons are consistent with their role in mediating vascular head pains and with the typical referral of such pains in man to the orbital region. This paper also presents preliminary results of recordings from rat trigeminal ganglion neurons activated by electrical stimulation of the middle meningeal artery and sagittal sinus. The latencies of activation of these neurons are indicative of conduction in slowly conducting myelinated axons and in unmyelinated axons. Some of the neurons could also be activated by mechanical stimuli applied to the vessels.     

Central mechanisms of respiratory rhythmogenesis

The organization and role of a respiratory neuronal generator as a part of the medullary respiratory center, including the role of afferent systems in the mechanisms of initiation and regulation of the center cyclic activity, are considered. Intrinsic organization of the respiratory generator and specific features of its functioning are analyzed, and the two main hypotheses concerning the mechanisms of rhythmic respiratory activity generation are discussed.Neirofiziologiya/Neurophysiology, Vol. 26, No. 3, pp. 230–236, May–June, 1994.     

Central mechanisms of fever.

The possible role of various potential chemical mediators in the production of fever is reviewed. A major problem in this field is the very considerable conflict of evidence, let alone interpretation. On the existing evidence, it appears unlikely that monoamines, acetyl choline, or alterations in relative concentrations of sodium and calcium play any major role in the production of fever. Recent evidence makes it unlikely that prostaglandins have a direct role in this mechanism, though the involvement of other metabolites of arachidonic acid has not been excluded. It is possible that protein synthesis may play a part in the central action of leukocyte pyrogen.     

Central mechanisms of sleep-wakefulness cycle

Brief anatomical, physiological and neurochemical basics of the regulation of wakefulness, slow wave (NREM) sleep and paradoxical (REM) sleep are regarded as representing by the end of the first decade of the second millennium.