A Role for Polymodal C-Fiber Afferents in Nonhistaminergic Itch

Department of Neurosurgery, Johns Hopkins University, Baltimore, Maryland 21287, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 07/2008; 28(30):7659-69. DOI: 10.1523/JNEUROSCI.1760-08.2008
Source: PubMed


Recent psychophysical and electrophysiological studies in humans suggest the existence of two peripheral pathways for itch, one that is responsive to histamine and a second pathway that can be activated by nonhistaminergic pruritogens (e.g., cowhage spicules). To explore the peripheral neuronal pathway for nonhistaminergic itch, behavioral responses and neuronal activity in unmyelinated afferent fibers were assessed in monkey after topical application of cowhage spicules or intradermal injection of histamine and capsaicin. Cowhage and histamine, but not capsaicin, evoked scratching behavior indicating the presence of itch. In single-fiber recordings, cowhage, histamine and/or capsaicin were applied to the cutaneous receptive field of 43 mechano-heat-sensitive C-fiber (CMH) nociceptors. The majority of CMHs exhibited a prolonged response to cowhage (39 of 43) or histamine (29 of 38), but not to capsaicin (3 of 34). Seven CMHs were activated by cowhage but not histamine. The average response to cowhage was more than twice the response to histamine, and responses were not correlated. The response of the CMHs to a stepped heat stimulus (49 degrees C, 3 s) was either quickly adapting (QC) or slowly adapting (SC). In contrast, the cowhage response was characterized by bursts of two or more action potentials (at approximately 1 Hz). The total cowhage response of the QC fibers (97 action potentials/5 min) was twice that of the SC fibers (49 action potentials/5 min). A subset of QC fibers exhibited high-frequency intraburst discharges ( approximately 30 Hz). These results suggest multiple mechanisms by which CMHs may encode itch to cowhage as well as pain to mechanical and heat stimuli.

Download full-text


Available from: Robert M Friedman,
  • Source
    • "Recent evidence suggests that chemical stimuli that elicit acute itch in humans and animals evoke action potentials in a specific subset of cutaneous nociceptors. These nociceptors, termed 'pruriceptive' because they respond to a pruritic agent, also respond to one or more noxious stimuli (Schmelz et al., 2003; Johanek et al., 2008; Ringkamp et al., 2011; Liu et al., 2012; Han et al., 2013). However, there is little information about whether activity in pruriceptive neurons might be abnormally generated during disorders that cause chronic itch. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Itch is a common symptom of diseases of the skin but can also accompany diseases of other tissues including the nervous system. Acute itch from chemicals experimentally applied to the skin is initiated and maintained by action potential activity in a subset of nociceptive neurons. But whether these pruriceptive neurons are active or might become intrinsically more excitable under the pathological conditions that produce persistent itch and nociceptive sensations in humans is largely unexplored. Recently, two distinct types of cutaneous nociceptive dorsal root ganglion neurons were identified as responding to pruritic chemicals and playing a role in itch sensation. One expressed the mas-related G-coupled protein receptor MRGPRA3 and the other MRGPRD (MRGPRA3(+) and MRGPRD(+) neurons, respectively). Here we tested whether these two distinct pruriceptive nociceptors exhibited an enhanced excitability after the development of contact hypersensitivity, an animal model of allergic contact dermatitis, a common pruritic disorder in humans. The characteristics of increased excitability of pruriceptive neurons during this disorder may also pertain to the same types of neurons active in other pruritic diseases or pathologies that affect the nervous system and other tissues or organs. We found that challenging the skin of the calf of the hind paw or the cheek of previously sensitized mice with the hapten, squaric acid dibutyl ester, produced symptoms of contact hypersensitivity including an increase in skin thickness and site-directed spontaneous pain-like (licking or wiping) and itch-like (biting or scratching) behaviours. Ablation of MRGPRA3(+) neurons led to a significant reduction in spontaneous scratching of the hapten-challenged nape of the neck of previously sensitized mice. In vivo, electrophysiological recordings revealed that MRGPRA3(+) and MRGPRD(+) neurons innervating the hapten-challenged skin exhibited a greater incidence of spontaneous activity and/or abnormal after-discharges in response to mechanical and heat stimuli applied to their receptive fields compared with neurons from the vehicle-treated control animals. Whole-cell recordings in vitro showed that both MRGPRA3(+) and MRGPRD(+) neurons from hapten-challenged mice displayed a significantly more depolarized resting membrane potential, decreased rheobase, and greater number of action potentials at twice rheobase compared with neurons from vehicle controls. These signs of neuronal hyperexcitability were associated with a significant increase in the peak amplitude of tetrodotoxin-sensitive and resistant sodium currents. Thus, the hyperexcitability of MRGPRA3(+) and MRGPRD(+) neurons, brought about in part by enhanced sodium currents, may contribute to the spontaneous itch- and pain-related behaviours accompanying contact hypersensitivity and/or other inflammatory diseases in humans.
    Brain 02/2014; 137(4). DOI:10.1093/brain/awu007 · 9.20 Impact Factor
  • Source
    • "Histamine-independent itch was first reported in 1953; papain and cowhage spicules were shown to induce the itch sensation [10]. The papain and cowhage spicules both activate polymodal C-fibers, which are in charge of pain sensation under mechanical and thermal stimuli as well [11]. The receptor target in this case is likely to be proteinase-activated receptor 2 (PAR2) [12], which can be activated by mast cell tryptase released from mast cells in both rat and human skin [13, 14]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: This study investigated whether immediate acupuncture effects in the acupoint are histamine dependent. Both histamine injection and manual acupuncture stimulation increased the pain threshold (PT) after treatment compared with the model group (P < 0.01), producing an analgesic effect. After pretreatment with clemastine, an H1 receptor antagonist and an antipruritic, the increase in the animals' pain threshold after acupuncture was suppressed compared with the Acu group (P < 0.01); however, there was no interference with the acupuncture-induced degranulation of mast cells. Pretreatment with disodium cromolyn did not suppress the increase in PT induced by the histamine injection at Zusanli (ST-36). We conclude that in adjuvant-induced arthritic rats, acupuncture analgesic effects are histamine dependent, and this histamine dependence determines the acupoint preference of acupoints away from the target site in acupuncture practice.
    Evidence-based Complementary and Alternative Medicine 11/2012; 2012:810512. DOI:10.1155/2012/810512 · 1.88 Impact Factor
  • Source
    • "DRG neurons were prepared from adult mice (~2 month old) by methods similar to those described previously [15,16]. Briefly, DRG from all spinal levels were collected in Ca2+/Mg2+-free Hanks' balanced salt solution (HBSS; Invitrogen) and treated with enzyme solution containing 60 units of papain/cystein (0.33 mg/mL), 5 mg/mL of Dispase, and 4 mg/mL of collagenase (Gibco) for 10 min at 37°C, respectively. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Imiquimod (IQ) is known as an agonist of Toll-like receptor 7 (TLR7) and is widely used to treat various infectious skin diseases. However, it causes severe itching sensation as its side effect. The precise mechanism of how IQ causes itching sensation is unknown. A recent report suggested a molecular target of IQ as TLR7 expressed in dorsal root ganglion (DRG) neurons. However, we recently proposed a TLR7-independent mechanism, in which the activation of TLR7 is not required for the action of IQ in DRG neurons. To resolve this controversy regarding the involvement of TLR7 and to address the exact molecular identity of itching sensation by IQ, we investigated the possible molecular target of IQ in DRG neurons. When IQ was applied to DRG neurons, we observed an increase in action potential (AP) duration and membrane resistance both in wild type and TLR7-deficient mice. Based on these results, we tested whether the treatment of IQ has an effect on the activity of K(+) channels, K(v)1.1 and K(v)1.2 (voltage-gated K(+) channels) and TREK1 and TRAAK (K(2P) channels). IQ effectively reduced the currents mediated by both K(+) channels in a dose-dependent manner, acting as an antagonist at TREK1 and TRAAK and as a partial antagonist at K(v)1.1 and K(v)1.2. Our results demonstrate that IQ blocks the voltage-gated K(+) channels to increase AP duration and K(2P) channels to increase membrane resistance, which are critical for the membrane excitability of DRG neurons. Therefore, we propose that IQ enhances the excitability of DRG neurons by blocking multiple potassium channels and causing pruritus.
    Molecular Pain 01/2012; 8(1):2. DOI:10.1186/1744-8069-8-2 · 3.65 Impact Factor
Show more