Noradrenergic regulation of itch transmission in the spinal cord mediated by α-adrenoceptors

It has recently been shown that clonidine suppresses itch-related responses via its action on α2-adrenoceptors in the spinal cord, raising the possibility that the descending noradrenergic system regulates itch signaling in the spinal cord. In this study, we investigated whether the transmission of itch signals in the spinal cord is under tonic inhibition by the descending noradrenergic system. An intraplantar injection of serotonin in mice induced biting of the treated paw (an itch-related response). An intrathecal injection of 6-hydroxydopamine (catecholaminergic neurotoxin) enhanced the itch-related response. There was a significant inverse correlation between the response and noradrenaline content. An intrathecal injection of phentolamine (α-adrenoceptor antagonist) enhanced serotonin-induced biting, although prazosin (α1-, α2B-, and α2C-adrenoceptor antagonist) and yohimbine (α2-adrenoceptor antagonist) had no effects. Intrathecal injections of phenylephrine (α1-adrenoceptor agonist) and clonidine (α2-adrenoceptor agonist) inhibited serotonin-induced biting. The action of phenylephrine was antagonized by intrathecal prazosin but not 5-methylurapidil (α1A-adrenoceptor antagonist), cyclazosin (α1B-adrenoceptor antagonist), and BMY 7378 (α1D-adrenoceptor antagonist). mRNAs encoding α1A-, α1B-, α2A-, α2B-, and α2C-adrenoceptor subtypes were expressed in the dorsal root ganglion and spinal dorsal horn. These results suggest that the descending noradrenergic system exerts tonic inhibition on itch signaling in the spinal cord. Both α1- and α2-adrenoceptors may be involved in the tonic inhibition of itch signaling and the stimulation of either α-adrenoceptor subtype may result in the inhibition of itch.

► Intrathecal injection of a catecholaminergic neurotoxin enhances itch.
► Intrathecal injection of alpha-adrenergic antagonist enhances itch.
► Intrathecal injections of alpha1- and alpha2-antagonists do not enhance itch.
► Intrathecal injections of alpha1- and alpha2-agonists inhibit itch.
► Intrathecal injection of a serotonergic neurotoxin does not enhance itch.