, 2002, Peters et al., 2002, Stucky et al., 1998, Suzuki et al., 2012 and Woo et al., 2012). A major current selleckchem challenge is defining the physiological properties of the neurons that form these two neurochemically distinct circumferential ending types. Therefore, each mouse hair follicle type receives a unique and

invariant combination of physiologically and morphologically distinct sensory neurons subtypes, making each hair follicle a distinctive mechanosensory end organ. However, these units do not function by themselves; they represent a cohort of exquisitely organized clusters containing one centrally located guard hair, about 20 surrounding awl/auchene hairs and about 80 interspersed zigzag hairs (Li et al., 2011) (Figure 3E). These clusters are organized in reiterative and partially overlapping patterns blanketing the mouse skin, highlighting a level

PD0325901 of complexity and sensitivity in hairy skin previously thought to only exist in glabrous skin. Nociceptors are uniquely tuned to stimuli that cause damage or threaten to cause damage and are found in both glabrous and hairy skin. Nociceptive neurons have been historically categorized by their stimulus response properties and more recently by their molecular profiles (Lallemend and Ernfors, 2012). High-threshold mechanoreceptors (HTMRs) are a broad category of mechanonociceptive sensory neurons that are optimally excited by noxious mechanical stimuli. HTMRs include Aδ and C free nerve endings that innervate the epidermis both in glabrous and hairy skin (Figure 1). Aδ-HTMRs, also known as A fiber mechanonociceptors (AM fibers), are

thought to mediate fast mechanical pain and can be further divided into fibers that respond to either noxious heat or cold stimuli. On the other hand, C-HTMRs respond solely to mechanical but not thermal stimuli (Bessou and Perl, 1969 and Cain et al., 2001). Nociceptors can be further categorized into two major neurochemical groups based on because neuropeptide expression. Those that contain neuropeptides, like substance P or CGRP, are referred as peptidergic nociceptors, whereas those that do not express neuropeptides are termed nonpeptidergic nociceptors and most exhibit binding to isolectin-B4 (Perry and Lawson, 1998 and Ribeiro-da-Silva et al., 1989). Their peripheral innervation patterns are segregated into unique patterns, with peptidergic neurons innervating basal regions of epidermis, while nonpeptidergic neurons innervate a more superficial epidermal region (Figures 1A and 1B). Differences in their peripheral distributions would suggest that peptidergic and nonpeptidergic C fibers differ in function. Indeed, pharmacological ablation of a population of nonpeptidergic neurons results in selective loss of sensitivity to noxious mechanical stimuli (Cavanaugh et al., 2009 and Zylka et al., 2005). Likewise, central terminal ablation of peptidergic neurons results in selective deficits in heat nociception (Cavanaugh et al., 2009).