Responsiveness of C Neurons in Rat Dorsal Root Ganglion to 5-Hydroxytryptamine-Induced Pruritic Stimuli In Vivo

Abstract

Hachisuka J, Furue H, Furue M, Yoshimura M. Responsiveness of C neurons in rat dorsal root ganglion to 5-hydroxytryptamine-induced pruritic stimuli in vivo. J Neurophysiol 104: 271-279, 2010. First published May 19, 2010 doi:10.1152/jn.00938.2009. Itching is a common symptom in dermatologic diseases and causes restless scratching of the skin, which aggravates the condition. The mechanism of the itch sensation, however, is enigmatic. The present study included behavioral tests and electrophysiological recordings from rat dorsal root ganglion (DRG) neurons in vivo to analyze the response to pruritic stimuli induced by topical application of 5-hydroxytryptamine (5-HT) to the skin. Topically applied 5-HT to the rostral back evoked scratching, whereas application of the vehicle did not. Following subcutaneous injection of the opioid receptor antagonist naloxone, the number of scratches decreased, suggesting that the scratching was preferentially mediated by itch but not pain sensation. To elucidate the firing properties of DRG neurons in response to topically applied 5-HT, intracellular recordings were made from DRG neurons in vivo. None of the A␤ and A␦ neurons responded to 5-HT; in contrast, 25 of 91 C neurons (27%) exhibited repetitive firing in response to 5-HT, which could be classified into two firing patterns: one was a transient type, characterized by low firing frequency that decreased within 5 min; the other was a long-lasting type, having high firing frequency that continued increasing after 5 min. The time course of the firing pattern of long-lasting C neurons was comparable to the scratching behavior. Intriguingly, the long-lasting-type neurons had a significantly smaller fast afterhyperpolarization than that of the 5-HTinsensitive neurons. These observations suggest that the long-lastingfiring C neurons in rat DRG sensitive to 5-HT are responsible for conveying pruritic information to the spinal cord.

Itch elicited by intradermal injection of serotonin, intracisternal injection of morphine, and their synergistic interactions in rats

“…We show that naloxone reduces the number of scratch bouts elicited by serotonin, a finding which has been previously shown for opioid receptor antagonists naloxone (Hachisuka et al, 2010) and naltrexone (Spradley et al, 2012). μ-Opioid receptor antagonists have been used to reduce itch produced by several pruritogens in a variety of human conditions (Phan et al, 2010).…”

“…Intradermal injections of serotonin into the cheek of rats elicited dose-dependent scratching with the hindlimb (Hachisuka et al, 2010; Klein et al, 2011) and, to a much lesser degree, wiping with the forelimb directed toward the site of injection (Fig. 1 A ).…”

“…In rats, mast cells release large amounts of serotonin (Gustafsson, 1980; Graziano, 1988; Purcell et al, 1989). In addition, topical application of serotonin activated a subpopulation of polymodal nociceptive DRG neurons with C axons and the duration of the responses of some of the recorded fibers matched the duration of scratching or biting evoked by the same stimulus in awake rats (Hachisuka et al 2010), suggesting that such C fibers play a role in production of itch. Intradermal injection of serotonin was also shown to elicit scratching of the nape of the neck and activity in lumbar dorsal horn neurons (Jinks and Carstens, 2002).…”

Molecular and cellular mechanisms that initiate pain and itch

“…Most of the 7 families of 5-HT receptors are GPCRs with the exception of 5-HT3R which is a ligand-gated ion channel. Topically applied 5-HT evokes a robust scratching in rats [115]. Direct i.d.…”

“…5-HT appears to initiate itch sensation by directly activating DRG neurons, since topically applied and intradermally injected 5-HT evoke action potential firing in C-type DRG neurons and spinal dorsal horn neurons, which is also evident by elevated expression of the c-fos protein in response to 5-HT application [115, 121]. Alpha-methylserotonin, a selective 5-HT2 receptor agonist, induces similar scratching behaviors in mice and the scratching induced by both 5-HT and α-methylserotonin is inhibited by a 5-HT2 receptor antagonist, ketanserin [122] which also attenuates experimental dry skin-induced chronic itch [123].…”