Local effector functions of capsaicin-sensitive sensory nerve endings : involvement of tachykinins, calcitonin gene-related peptide and other neuropeptides

The results of neural tracing studies suggest that vagal afferent fibers in cervical and thoracic branches innervate the esophagus, lower airways, heart, aorta, and possibly the thymus, and via abdominal branches the entire gastrointestinal tract, liver, portal vein, billiary system, pancreas, but not the spleen. In addition, vagal afferents innervate numerous thoracic and abdominal paraganglia associated with the vagus nerves. Specific terminal structures such as flower basket terminals, intraganglionic laminar endings and intramuscular arrays have been identified in the various organs and organ compartments, suggesting functional specializations. Electrophysiological recording studies have identified mechano- and chemo-receptors, as well as temperature- and osmo-sensors. In the rat and several other species, mostly polymodal units, while in the cat more specialized units have been reported. Few details of the peripheral transduction cascades and the transmitters for signal propagation in the CNS are known. Glutamate and its various receptors are likely to play an important role at the level of primary afferent signaling to the solitary nucleus. The vagal afferent system is thus in an excellent position to detect immune-related events in the periphery and generate appropriate autonomic, endocrine, and behavioral responses via central reflex pathways. There is also good evidence for a role of vagal afferents in nociception, as manifested by affective-emotional responses such as increased blood pressure and tachycardia, typically associated with the perception of pain, and mediated via central reflex pathways involving the amygdala and other parts of the limbic system. The massive central projections are likely to be responsible for the antiepileptic properties of afferent vagal stimulation in humans. Furthermore, these functions are in line with a general defensive character ascribed to the vagal afferent, paraventricular system in lower vertebrates.

Functional and chemical anatomy of the afferent vagal system.

Activity-dependent neuronal plasticity following tissue injury and inflammation

Capsaicin-sensitive sensory neurons convey to the central nervous system signals (chemical and physical) arising from viscera and the skin which activate a variety of visceromotor and neuroendocrine reflexes integrated at various levels (intramurally in peripheral organs, at level of prevertebral ganglia, spinal and supraspinal level). Much evidence is now available that peripheral terminals of certain sensory neurons, widely distributed in skin and viscera have the ability to release, upon adequate stimulation, their transmitter content. In addition to the well-known "axon reflex" arrangement, the capsaicin-sensitive sensory neurons have the ability to release the stored transmitter also from the same terminal which is excited by the environmental stimulus. The efferent function of these sensory neurons is realized through the direct and indirect (i.e. mediated by activation of other cells) effects of released mediators. The action of released transmitters on postjunctional elements covers a wide range of effects which may have a physiological or pathological relevance. Development of drugs capable of controlling the sensory-efferent functions of the capsaicin-sensitive sensory neurons represent a new and very promising area of research for pharmacological treatment of various human diseases.

The sensory-efferent function of capsaicin-sensitive sensory neurons

Immunohistochemical distribution of somatostatin-like immunoreactivity in the central nervous system of the adult rat

Biochemical and anatomical observations on the degeneration of peptide-containing primary afferent neurons after neonatal capsaicin.

The mode of termination of primary afferent fibres within the superficial dorsal horn of the spinal cord was studied with anterograde tracing methods in normal rats and in animals which had been treated with capsaicin (50 mg/kg. s.c.) shortly after birth. In normal animals following injections of horseradish peroxidase (HRP) into lumbar dorsal root ganglia L4, L5, L6, a Golgi-like filling of primary afferent fibres was seen consistently within laminae I, II, and III of the dorsal horn. Several types of lamina related arborisations were observed, depending upon the survival time after HRP injection. At the earliest survival time (1–2 days) a punctate granular labelling was found in laminae I and II inner (IIi). At 3 days survival a Golgi like labelling of primary afferent axons occurred and three tiers of arborisation were seen within laminae I, II outer (IIO), and II inner (IIi), respectively. By 7 days after injection this pattern was considerably reduced and there was coarser fibre labelling within laminae I, IIO, and III.



When these tracing experiments were repeated in capsaicin-treated rats in which up to 90%of unmyelinated fibres had been destroyed, evidence for a considerable loss of some inputs and rearrangement of the remaining fibres was found. At 3–5 days survival the axonal labelling within laminae I and IIi was severely depleted yet some input, particularly to lamina IIO, was present. At 7 days survival deep fibre labelling within lamina III now extended well into lamina II.



Mapping of the primary afferent input following 3H-proline injections into the dorsal root ganglion and subsequent autoradiographic processing confirmed that primary afferents terminated throughout the dorsal horn but most heavily in two bands within laminae I and IIi. These two dense layers of termination were not present in capsaicin-treated animals, suggesting that they corresponded to areas of unmyelinated primary afferent fibre input.



These data, taken together with histochemical observations on the distribution of substance P and fluoride-resistant acid phosphatase (FRAP)-containing primary afferents, suggests that the earliest-labelled fibre systems (3days) were unmyelinated and replaced at 7 days by predominantly A6 myelinated fibres. It is further suggested that of the three tiers of C fibre terminations seen at 3 days, the most superficial corresponds in part to those primary afferents that can be stained for substance P within lamina I while the most ventral tier within lamina IIi are those primary afferents containing FRAP. The presence of the two temporally distinct fibre systems also suggests that laminae I and IIo, receive both C and A6 primary afferent input while lamina IIi, receives only C fibre input.

S. P. Hunt

Papers

Biochemical and anatomical observations on the degeneration of peptide-containing primary afferent neurons after neonatal capsaicin.

The termination of primary afferents within the rat dorsal horn: evidence for rearrangement following capsaicin treatment.