Descending Control of Itch Transmission by the Serotonergic System via 5-HT1A-Facilitated GRP-GRPR Signaling

Abstract

SUMMARY Central serotonin (5-HT) modulates somatosensory transduction, but how it achieves sensory modality-specific modulation remains unclear. Here we report that enhancing serotonergic tone via administration of 5-hydroxytryptophan potentiates itch sensation, whereas mice lacking 5-HT or serotonergic neurons in the brainstem exhibit markedly reduced scratching behavior. Through pharmacological and behavioral screening, we identified 5-HT1A as a key receptor in facilitating gastrin-releasing peptide (GRP)-dependent scratching behavior. Co-activation of 5-HT1A and GRP receptors (GRPR) greatly potentiates subthreshold, GRP-induced Ca2+ transients and action potential firing of GRPR+ neurons. Immunostaining, biochemical and biophysical studies suggest that 5-HT1A and GRPR may function as receptor heteromeric complexes. Furthermore, 5-HT1A blockade significantly attenuates, whereas its activation contributes to, long-lasting itch transmission. Thus, our studies demonstrate that the descending 5-HT system facilitates GRP-GRPR signaling via 5-HT1A to augment itch-specific outputs and a disruption of crosstalk between 5-HT1A and GRPR may be a useful anti-pruritic strategy.

HTR7 Mediates Serotonergic Acute and Chronic Itch

“…Pharmacological and genetic ablation studies have shown that HTR1a, HTR1b, HTR2a, HTR2b and HTR3a mediate some forms of acute and inflammatory pain transmission (Abbott et al, 1996; Kayser et al, 2007; Lin et al, 2011; Nojima and Carstens, 2003; Van Steenwinckel et al, 2008; Zeitz et al, 2002). Pharmacological studies have also implicated peripheral HTR2a, HTR2b and HTR3 receptors, and central HTR1a receptors in itch (Bonnet et al, 2008; Imamachi et al, 2009; Kyriakides et al, 1999; Liu et al, 2013; Zhao et al, 2014), but to date there has been no genetic evidence for any 5-HT receptor in transducing serotonergic itch signals in primary afferent neurons. We have used genetic and pharmacological tools to show that HTR7 plays a selective role in acute serotonergic and atopic dermatitis itch, but not pain.…”

Inhibition of the mammalian target of rapamycin complex 1 signaling pathway reduces itch behaviour in mice

“…12 In addition, recent research has suggested that the GRP-GRPR pathway is primarily engaged in transducing nonhistaminergic acute itch sensation and may play a relatively minor role in histaminergic itch. 46 Peripheral activation of dorsal horn neurons that express GRPR was also shown to be mediated through C-fibers and to involve glutamate release, although some Ad fiber signaling was also reported. 20 However, the location of GRP-immunoreactive neurons in neural circuits mediating itch remains controversial.…”

Peripheral and spinal 5-HT receptors participate in cholestatic itch and antinociception induced by bile duct ligation in rats

“…Among monoamine neurotransmitters, serotonin, or 5-hydroxytryptamine (5-HT), is considered to play key and complex role in pain sensation25, and recently it was also demonstrated its crucial role in itch sensation26. To date, seven classes of 5-HT receptors (5-HT 1 -5-HT 7 ) have been identified and comprise at least 15 subtypes25.…”

“…Except 5-HT 3 receptor as a ligand-gated cation channel, all other 5-HT receptors are G protein-coupled receptors (GPCRs)25. As 5-HT is not able to penetrate the blood-brain-barrier (BBB), peripheral and central 5-HT systems are considered to be separated compartments and employ distinct rate-limiting enzymes for 5-HT synthesis, such as tryptophan hydroxylase 1 ( Tph1 ) in the skin and tryptophan hydroxylase 1 ( Tph2 ) in the brain26. 5-HT in the skin released from mast cells, as a critical component of “inflammatory soup”, was identified as a potent inducer of pain or itch via activation distinct 5-HT receptors subtypes, such as 5-HT 2A , 5-HT 2B , 5-HT 2C , 5-HT 3 , 5-HT 4 , 5-HT 6 , and 5-HT 7 272829.…”