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: 2.72). 02/2008; 75(1):138-145. DOI: 10.1016/j.brainresbull.2007.08.003


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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Available from: Dong-Yuan Cao, May 17, 2014
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    • "The release of SP during acupuncture and its influence on neurons across segments have been proven experimentally by Zhang et al. [25, 26]. The degranulation of histamine from mast cells was also proven to play an important role in the analgesic effects of acupuncture [27]. "
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    ABSTRACT: According to the classic theory of Chinese medicine, pain is due to the blockage in meridian channels, and acupuncture was invented to treat pain by "dredging" the channels. To test the theory, a hyperalgesia model was made by injecting hydrogel into low hydraulic resistance channel (LHRC) in 12 anaesthetized minipigs. Tail-flick threshold and ear-flick threshold were measured using a thermal radiation dolorimeter, and relative flick threshold (RFT) was calculated. Hydraulic resistance (HR) was measured with a biological HR measuring instrument on low HR points on LHRC and on control points with higher HR located outside LHRC; readings were recorded before, during, and after acupuncture treatment. RFT decreased after blocking the LRHC and was still significantly decreased 2 days and 4 days afterwards. No significant changes occurred when injecting saline into the same points or injecting gel into points outside the channel. Subsequent acupuncture reduced HR on LRHC along meridians but had no significant effect on sites with higher HR located outside LHRC. One of the mechanisms of action of acupuncture treatment for chronic pain may be that acupuncture affects peripheral tissue by reducing the HR in LHRC along meridians, improving the flow of interstitial fluid and removing algogenic substances and thereby relieving pain.
    Evidence-based Complementary and Alternative Medicine 08/2013; 2013:654645. DOI:10.1155/2013/654645 · 1.88 Impact Factor
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    • "(b) illustrates putative communication between adjacent branches of nerves from different spinal segments via neuroactive mediators released by acupuncture stimulation from neural and non-neuronal tissues. (b) was reproduced based on the work done by Professor Zhao's research group with his generous permission (also see [20, 21, 224]). "
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    ABSTRACT: When an acupuncture needle is inserted into a designated point on the body and mechanical or electrical stimulation is delivered, various neural and neuroactive components are activated. The collection of the activated neural and neuroactive components distributed in the skin, muscle, and connective tissues surrounding the inserted needle is defined as a neural acupuncture unit (NAU). The traditionally defined acupoints represent an anatomical landmark system that indicates local sites where NAUs may contain relatively dense and concentrated neural and neuroactive components, upon which acupuncture stimulation would elicit a more efficient therapeutic response. The NAU-based local mechanisms of biochemical and biophysical reactions play an important role in acupuncture-induced analgesia. Different properties of NAUs are associated with different components of needling sensation. There exist several central pathways to convey NAU-induced acupuncture signals, Electroacupuncture (EA) frequency-specific neurochemical effects are related to different peripheral and central pathways transmitting afferent signals from different frequency of NAU stimulation. More widespread and intense neuroimaging responses of brain regions to acupuncture may be a consequence of more efficient NAU stimulation modes. The introduction of the conception of NAU provides a new theoretical approach to interpreting effects and mechanisms of acupuncture in modern biomedical knowledge framework.
    Evidence-based Complementary and Alternative Medicine 03/2012; 2012(3):429412. DOI:10.1155/2012/429412 · 1.88 Impact Factor
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    • "It could be a useful as an alternative to morphine, because spinal TY005 appears to be more effective at attenuating mechanical allodynia than morphine while retatining antinociceptive efficacy. Recent findings in rodent models have suggested that SP and NK1 receptor activation have a role in temporomandibular joint pain and inflammation (Takeda et al., 2005), and this has been supported by further studies where similar mechanisms have been proposed (Torsney and MacDermott 2006; Zhang et al., 2008). Sustained administration of opioids can lead to the development of antinociceptive tolerance (Ossipov et al., 2005), so higher doses need to be administered to achieve adequate pain relief. "
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    ABSTRACT: The use of opioids in treating pain is limited due to significant side effects including somnolence, constipation, analgesic tolerance, addiction and respiratory depression. Pre-clinical studies have shown that neurokinin 1 (NK(1) ) receptor antagonists block opioid-induced antinociceptive tolerance and may inhibit opioid-induced rewarding behaviours. Here, we have characterized a bifunctional peptide with both opioid agonist and NK(1) antagonist pharmacophores in a rodent model of neuropathic pain. Rats were evaluated for behavioural responses to both tactile and thermal stimuli in either an uninjured, sham- or nerve-injured state. TY005 (Tyr-DAla-Gly-Phe-Met-Pro-Leu-Trp-O-3,5-Bn(CF(3) )(2) ) was delivered spinally or systemically to assess the antinociceptive effects after acute exposure. Motor skills were evaluated using the rotarod test to determine potential sedative effects. Spinal TY005 was given chronically to sham- or nerve-injured animals to determine the development of tolerance. Bolus injections of TY005 produced dose-dependent antinociception in non-injured animals and alleviated nerve injury-induced thermal and tactile hypersensitivities (i.e. antihyperalgesia) more effectively than morphine. Sedative effects were not evident from the rotarod test at doses that were antihyperalgesic, nor at doses threefold higher. Repeated administration of TY005 did not lead to the development of antihyperalgesic tolerance or alter sensory thresholds. Collectively, the data suggest that opioid agonist/NK(1) antagonist bifunctional peptides represent a promising novel approach to the management of chronic pain without the development of tolerance, reducing the need for escalation of doses and unwanted side effects associated with opiates alone.
    British Journal of Pharmacology 11/2010; 161(5):986-1001. DOI:10.1111/j.1476-5381.2010.00824.x · 4.84 Impact Factor
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