Tonic Inhibition of Allergic Itch Signaling by the Descending Noradrenergic System in Mice

Abstract

Itch is a common complaint among patients with cutaneous diseases. H 1 histamine receptor antagonists are the drugs of choice for the treatment of itch, but their effect in ameliorating many pruritic diseases including atopic dermatitis is often unsatisfactory. The reason for this may be due in part to the presence of many itch mediators other than histamine (1), and therefore specific antagonists and inhibitors may not effectively relieve many kinds of pruritic diseases. Although at least two subpopulations of primary afferents (histamine sensitive and insensitive) are involved in itch signaling (2), the types of neurotransmitters involved in itch signaling in the dorsal horn may be far fewer than those of itch mediators in the skin. It was recently reported that gastrin-releasing peptide plays an important role in itch signaling from sensory neurons to the interneurons in the dorsal horn (3). Ablation of dorsal horn neurons expressing gastrin-releasing peptide receptor has been shown to result in the suppression of itch-related responses to histamine and several other itch mediators (3). This raises the possibility that administration of antipruritic agents that act on the dorsal horn will be effective for the treatment of itch of many pruritic diseases.We have recently found that clonidine suppresses the itch-related response of mice to an intradermal injection of serotonin through its action on the α 2 -adrenoceptors in the spinal cord (4). In mice, cyproheptadine, a serotonin and histamine antagonist, inhibits the itch-related response to serotonin, but does not inhibit the response to mosquito allergy (5, 6). Acute topical application of tacrolimus inhibits itch-related responses to mosquito allergy and proteinase-activated receptor-2 (PAR 2 ) agonist, but does not inhibit the responses to serotonin and histamine (7). Itch signals induced by mosquito allergy may be mediated by primary afferents expressing PAR 2 receptors (8). These findings taken together suggest that itch signals of mosquito allergy and serotonin are mediated by separate primary afferents. Therefore, in order to determine whether the stimulation of α 2 -adrenoceptor in the spinal cord would suppress itch induced by different causes, we investigated whether intrathecal clonidine would suppress the itch-related response to mosquito allergy. The descending noradrenergic system exerts tonic inhibition on pain transmission in the dorsal horn mediated by α-adrenoceptors (9, 10). Thus, we also investigated whether the descending monoaminergic systems exert a tonic inhibition on the transmission of itch signals in the spinal cord.Male ICR mice (6 -12-weeks-old; Japan SLC, Shizuoka) were used. They were kept in a room under controlled temperature (22 ± 1°C), humidity (55 ± 10%), and light (light on 7:00 -19:00 h). Food and water were Toyama 930-0194, Japan Received November 29, 2010; Accepted December 30, 2010 Abstract. We investigated whether the descending noradrenergic system regulates allergic itch. Mosquito allergy of the hind paw elici...

Milnacipran Inhibits Itch-Related Responses in Mice Through the Enhancement of Noradrenergic Transmission in the Spinal Cord

“…Because the antipruritic action of systemically administered milnacipran was reversed by intrathecal phentolamine, the effect of milnacipran is thought to be because of inhibited noradrenaline reuptake in the spinal dorsal horn. Intrathecal phentolamine (1.0 mg/site) increases itchrelated behavior in normal mice (3,4). In the present experiments, intrathecal phentolamine at the same dose inhibited the milnacipran action, but itchrelated behavior did not exceed a normal level.…”

“…Recently, we have found the descending noradrenergic system to exert a tonic inhibition of itch signaling in the spinal cord through aadrenoceptors (3,4). Stimulation of either a 1 adrenoceptor or a 2 adrenoceptor in the spinal cord results in marked reduction in itchrelated behavior in mice (3,5).…”

Methods for Preclinical Assessment of Antipruritic Agents and Itch Mechanisms Independent of Mast-Cell Histamine

“…46,47) The α 2 -adrenoceptor agonist clonidine and the serotonin-noradrenaline reuptake inhibitor milnacipran inhibited pruritogen-induced biting through their action on the spinal cord. 48,49) Under normal conditions, the descending serotonergic system does not seem to exert tonic inhibition of itch transmission.…”

“…48,49) Under normal conditions, the descending serotonergic system does not seem to exert tonic inhibition of itch transmission. 47) …”

TRP Channels and Pruritus

“…Recently, a subpopulation of inhibitory interneurons expressing the transcription factor Bhlhb5 during the development was identified as the mediator of the pain evoked itch inhibition [11]. Furthermore, descending adrenergic pathways were also suggested to control the inhibitory interneurons of the spinal cord [32,33].…”