Itchy skin conditions affect a substantial portion of the US population at annual costs exceeding $100 billion. Most types of chronic itch are poorly managed, establishing a compelling need to develop more effective mechanisms-based treatments for these debilitating conditions. The present proposal will investigate the role of neurons located in the rostral ventromedial medulla (RVM) that express the receptor for substance P (i.e., NK-1R) in descending modulation of itch, as well as the role of NK-1R-expressing neurons in the superficial spinal and medullary dorsal horn in the ascending transmission of itch. The proposal has two overarching aims.
Specific Aim 1 hypothesizes that NK-1R-expressing neurons, and specifically ON-cells in the RVM (i.e., those that fire just prior to a noxious stimulus-evoked withdrawal response), are critically involved in descending inhibition of spinal itch transmission. We will employ chemogenetic and intracranial microinjection approaches to test if activation of NK-1R-expressing RVM neurons suppresses acute pruritogen-evoked itch behavior, or manifestations of chronic itch (spontaneous and touch-evoked scratching) in mouse models of psoriasis and atopic dermatitis itch. We will also investigate NK- 1R-mediated descending inhibition of spinal itch-transmitting neurons. Finally, we will record from optogenetically identified NK-1R-expressing neurons in RVM and functionally establish if they are ON cells.
Specific Aim 2 hypothesizes that NK-1R-expressing neurons in the superficial spinal/ medullary dorsal horn give rise to ascending projections to the somatosensory thalamus and parabrachial nucleus that are critically involved in transmitting itch-related signals. We will use an optogenetic approach to determine if NK-1R- expressing neurons in the spinal/medullary dorsal horn are activated by pruritogenic stimuli, and opto- and chemogenetic approaches to investigate if the activation of such neurons elicits behavioral signs of itch (and/or pain). A better understanding of central itch modulation and ascending sensory transmission has translational significance for developing novel antipruritic treatments targeting NK-1 receptors to increase descending inhibition of itch and reduce ascending itch-related signals. Page 1
Chronic itch represents a significant health and socioeconomic burden, affecting a large proportion of the US and world population. The present proposal will use preclinical mouse models to investigate the mechanisms that underlie the descending modulation of itch from the brainstem, as well as ascending transmission of itch signals from the spinal cord to higher centers, with an emphasis on neurons that express the receptor for substance P (NK-1 receptor). A better understanding of descending modulation and ascending transmission of itch has translational significance for the mechanisms-based development of more effective treatments for chronic itch, particularly those targeting the NK-1 receptor.
