Paracrine-like excitation of low-threshold mechanoceptive C-fibers innervating rat hairy skin is mediated by substance P via NK-1 receptors

Faculty of Pharmacology, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, PR China
Brain Research Bulletin (Impact Factor: 2.97). 02/2008; DOI: 10.1016/j.brainresbull.2007.08.003

ABSTRACT We reported previously that C-fibers innervating rat skin can be excited by short trains of electrical shocks (‘tetanus’) applied to neighboring nerves. Since these nerves were disconnected from the CNS, the cross-talk is located peripherally. Here we tested if low-threshold mechanoceptive (LTM) C-fibers can be excited by this cross-talk and if this process is mediated by substance P (SP) via neurokinin-1 (NK-1) receptors. In urethane anesthetized rats we found that 80% (56/71) of LTM C-fibers, recorded in the lateral cutaneous branch of the dorsal ramus (CBDR) of T10 spinal nerve, were excited by a 10 s, 20 Hz tetanus of the T9 CBDR. Compared to the spontaneous pre-tetanic firing frequency of 1.62 ± 0.40 impulses/30 s, the frequency significantly increased to 3.74 ± 0.99, 3.17 ± 0.69 and 2.92 ± 0.63 impulses/30 s, at 30, 60 and 90 s after the tetanus, respectively, and declined to the baseline frequency thereafter. When injected into their receptive fields, SP mimicked the tetanically induced increase of firing rate, whereas the NK-1 receptor antagonist WIN 51708 blocked the excitation in most fibers. The excitation was significantly diminished in adult rats that were neonatally treated with capsaicin, a treatment that destroys most SP-expressing afferent fibers. Thus, we conclude that peptidergic primary afferents are functionally linked with adjacent LTM C-fibers in a non-synaptic, paracrine-like signaling pathway via SP and NK-1 receptors, and perhaps also other agents as well. We propose that this cross-talk has evolved as a mechanism regulating the mechanoceptive characteristics of LTM C-fibers, presumably contributing to pain sensation elicited by tactile stimuli (‘allodynia’).

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    ABSTRACT: The human hairy skin is innervated by a very ancient system of slow-conducting low-threshold mechanoreceptors termed C-tactile fibres (CTs). Intriguingly, even the existence of CTs in the distal limbs (non-hairy/glabrous skin) remains to be established, let alone their functional significance in the neural system. In this thesis, we examined the function of CTs through the prism of pain and its multifarious expressions, in particular touch-evoked pain (allodynia). In Paper I, we showed that the deep somatic pain generated by infusion of hypertonic saline (HS: 5%) into the tibialis anterior muscle is enhanced by concurrent application of vibration (200 Hz- 200 μm) and brushing (1.0 and 3.0 cm s-1) to the overlying hairy skin. In Paper II, we demonstrated that a comparable expression of allodynia elicits when vibration and brushing are applied across skin types and spinal segments – glabrous skin of fingers and hairy skin of dorsal forearm – during HS-infusion into the flexor carpi ulnaris muscle. In Paper III, we showed that vibration evokes pain/allodynia following eccentric exercise-induced muscle soreness (no resting pain). Furthermore, a cognate expression of touch-evoked allodynia was observed in a clinical subject with activity-triggered heel-pain without exposure to eccentric exercise. In Paper IV, we demonstrated that, in the presence of HS-induced cutaneous pain, the application of vibration to an adjacent region of skin generates allodynia. In all four papers, the vibration- and brush-evoked allodynia persisted following conduction block of myelinated afferents by compression. In contrast, the effect was abolished during conduction block of cutaneous C fibres by injecting a local anaesthetic into the skin stimulation by vibration. Collectively these psychophysical observations provide the first human evidence that CTs arising from hairy skin, and their functional counterparts in glabrous skin, contribute to mechanical allodynia. This phenomenon appears to be reproducible in rapid-onset (HS-induced), delayed-onset (exercise-induced) and clinical pain conditions.
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