Primary Afferent Peptides

Administration of high doses of capsaicin to the rat by the subcutaneous route was the first procedure by which an effect on spinal cord substance P was found. It is noteworthy that this work, conducted by Gasparovic et al. (1964), preceded by many years the current surge of interest in capsaicin. Using a bioassay for substance P, they showed that capsaicin reduced the content of this peptide in whole spinal cord but did not alter that of whole brain. This has recently been confirmed by Jessell et al. (1978) who, using radioimmunoassay techniques, found a 48% reduction in the levels of spinal cord dorsal horn substance P. Similar results have since been obtained by Gamse et al. (1980a,fe). In addition they reported reduced substance P content of dorsal roots, dorsal root 

The mechanism whereby capsaicin treatment of adult animals brings about a loss of peptides from sensory nerves is not clear. The possibilities include degeneration of those neurons, interference with terminal storage capacity, inhibition of peptide synthesis, or blockade of axonal transport. As described earlier, there is no evidence for capsaicin-induced degeneration after subcutaneous treatment of adult animals. This is supported by the observation that peptide levels partially recover in affected areas some time after treatment (Gamse et al., 19806). The results obtained after intrathecal treatment suggest a direct effect on primary afferent terminals 

Finally, in the rat the capability of a single dose of capsaicin to reduce tissue levels of substance P diminishes as animals mature, neonates being maximally susceptible (Gamse et al., 1980a). The gradual failure in the potency of capsaicin with ontogenesis parallels the time course of the anatomically observed reduction in susceptibility of sensory neurons to capsaicin-induced degeneration (see Section 5). This is consistent with the conclusion that substance P loss after treatment of neonates with capsaicin 

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Several lines of investigation have provided evidence to support the theory that CGRP plays a role in migraine. CGRP is the most abundant primary afferent peptide in trigeminal sensory nerves. Since CGRP is one of the most potent vasodilators known and the CGRP receptor is... 

The neuropeptides are peptides acting as neurotransmitters. Some form families such as the tachykinin family with substance P, neurokinin A and neurokinin B, which consist of 11 or 12 amino acids and possess the common carboxy-terminal sequence Phe-X-Gly-Leu-Met-CONH2. Substance P is a transmitter of primary afferent nociceptive neurones. The opioid peptide family is characterized by the C-terminal sequence Tyr-Gly-Gly-Phe-X. Its numerous members are transmitters in many brain neurones. Neuropeptide Y (NPY), with 36 amino acids, is a transmitter (with noradrenaline and ATP) of postganglionic sympathetic neurones. 

A5 and C primarily project to lamina II and V of the dorsal horn, where they synapse onto local interneurons or directly onto upward-projecting neurons (figure 8.1). These primary afferents release a number of neurotransmitters to relay pain, including glutamate, aspartate, substance P, neurokinin A and B, and calcitonin gene-related peptide (table 8.1). NMDA, non-NMDA and neurokinin receptors are involved in re-... 

Stimulation of 5-HT4 receptors on the presynaptic terminal of submucosal intrinsic primary afferent nerves enhances the release of their neurotransmitters, including calcitoningene-related peptide, which stimulate second-order enteric neurons to promote the peristaltic reflex (Figure 62-4). These enteric neurons stimulate proximal bowel contraction (via acetylcholine and substance P) and distal bowel relaxation (via nitric oxide and vasoactive intestinal peptide). 

Surprisingly, the vanilloid receptor ligand capsaicin supplied the first experimental evidence for the association between SP and nociception (Gasparovic et al., 1964). Capsaicin depletes small primary afferents of at least SP, if not all of their peptide content, and this was accompanied by hypoalgesia. SP depolarizes the ventral root of an isolated rat spinal cord preparation (Konishi and Otsuka, 1974), and has also been shown to excite and/or depolarize neurons in the dorsal root (Urban et al., 1985). Furthermore, in studies on the larger laminae IV and V neurons, the selective agonist, [Sar9,... 

Li D, Ren Y, Xu X, Zou X, Fang L, Lin Q (2008) Sensitization of primary afferent nociceptors induced by intradermal capsaicin involves the peripheral release of calcitonin gene-related peptide driven by dorsal root reflexes. J Pain 9 1155-1168 Li DP, Chen SR, Pan YZ, Levey Al, Pan HL (2002a) Role of presynaptic muscarinic and GABAB receptors in spinal glutamate release and cholinergic analgesia in rats. J Physiol (Lond) 543 807-818... 

In conclusion, data from biochemical, physiological/pharmacological and immunocyto-chemical studies concur in supporting Glu as a primary afferent neurotransmitter. Although it cannot be excluded that a subpopulation of primary afferent terminals that have escaped investigation transmit their signals by other means, the available evidence speaks strongly in favor of Glu as a transmitter in most, if not all, primary afferent terminals (Fig. 4). This of course does not exclude that other compounds, e.g. peptides, are co-released with Glu from selected populations of primary afferent terminals. 

Galeazza MT, Garry MG, Yost HJ, Strait KA, Hargreaves KM, Seybold VS (1995) Plasticity in the synthesis and storage of substance P and calcitonin gene-related peptide in primary afferent neurons during peripheral inflammation. Neuroscience 66 443-458... 

Eischer, A., McGregor, G. P., Saria, A., Philippin, B., and Kummer, W. (1996). Induction of tachykinin gene and peptide expression in guinea pig nodose primary afferent neurons by allergic airway inflammation. J. Clin. Invest. 98, 2284-2291. 

Opioid receptors are also located presynaptically on primary afferents (type C and Ag fibers) in the dorsal horn of the spinal cord. Activation of these receptors —release of substance P, a peptide neurotransmitter that causes excitatory actions in pain pathways. Opioid receptors involved in spinal analgesia are of both p and K subtypes. 

Substance P, an undecapeptide, is a member of the tachykinin peptide group. It is an important sensory neuron transmitter in the ENS and, of course, in primary afferents involved in nociception. Substance P contracts intestinal and bronchiolar smooth muscle but is an arteriolar vasodilator (possibly via NO release). It may also play a role in renal and salivary gland functions. 

Nagy, J. I., Hunt, S. P., Iversen, L. L., and Emson, P. C., 19816, Biochemical and anatomical observations on the degeneration of peptide-containing primary afferent neurons after neonatal capsaicin. Neuroscience, 6 1923-1934. 

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