miR-183 cluster scales mechanical pain sensitivity by regulating basal and neuropathic pain genes

Abstract

Nociception is protective and prevents tissue damage but can also facilitate chronic pain. Whether a general principle governs these two types of pain is unknown. Here, we show that both basal mechanical and neuropathic pain are controlled by the microRNA-183 (miR-183) cluster in mice. This single cluster controls more than 80% of neuropathic pain-regulated genes and scales basal mechanical sensitivity and mechanical allodynia by regulating auxiliary voltage-gated calcium channel subunits α2δ-1 and α2δ-2. Basal sensitivity is controlled in nociceptors, and allodynia involves TrkB light-touch mechanoreceptors. These light-touch-sensitive neurons, which normally do not elicit pain, produce pain during neuropathy that is reversed by gabapentin. Thus, a single microRNA cluster continuously scales acute noxious mechanical sensitivity in nociceptive neurons and suppresses neuropathic pain transduction in a specific, light-touch-sensitive neuronal type recruited during mechanical allodynia.

The miR-183/96/182 Cluster Regulates Macrophage Functions in Response to <b><i>Pseudomonas aeruginosa</i></b>

“…It was originally identified as a sensory organ-specific miRNA cluster [7, 8]. We and others have shown that miR-183/96/182 is required for the normal function of all major sensory organs, including vision [8], hearing and balance [8-10], olfaction [11], and pain [12]. Recently, mounting evidence from our group and others demonstrated that member(s) of miR-183/96/182 are also expressed and play important roles in both innate [13-16] and adaptive immune systems [17-19], suggesting that miR-183/96/182 provides one of the first shared genetic links between the immune and traditional sensory systems, supporting the recently emerging concept of the immune system as a sensory system [20].…”

Control of mechanical pain hypersensitivity through ligand-targeted photoablation of TrkB positive sensory neurons

“…Thus, mechanical pain arising from neuropathy or tissue inflammation is likely mechanistically different and should therefore be treated as a distinct clinical entity. Of note, the neurons marked in the TrkB CreERT2 line do not express C-fiber markers such as IB4, CGRP and Vglut3, but overlap with markers of A-fibers, all of which have previously been implicated in mechanical allodynia (Abrahamsen et al, 2008;Ossipov et al, 2002a;Ossipov et al, 2002b;Peng et al, 2017;Seal et al, 2009;Tarpley et al, 2004;Xu et al, 2015). A future challenge will be to determine whether mechanical hypersensitivity is conveyed by only Aδ-LTMR's or RA Aβ−LTMR's fibers, or whether both afferent types are required.…”

“…We further reasoned that manipulation of TrkB+ neurons through loss and gain of function experiments would also allow us to identify the peripheral neuron type which inputs mechanical hypersensitivity into the spinal cord. Both nociceptors and LTMRs have been implicated in mechanical allodynia but consensus on the sufficiency and necessity of a specific subpopulation of neurons that conveys this sensation is lacking (Abrahamsen et al, 2008;Ossipov et al, 2002a;Ossipov et al, 2002b;Peng et al, 2017;Seal et al, 2009;Tarpley et al, 2004;Xu et al, 2015). We found that TrkB+ LTMRs were required for hypersensitivity to both punctate and dynamic mechanical stimuli after nerve injury, and that optogenetic activation of TrkB+ neurons was sufficient to evoke strong nocifensive behavior.…”

“…However, allodynia persists even when these neurons fail to develop (Lou et al, 2013), and recent evidence indicates that transient Vglut3 expression in spinal interneurons accounts for the phenotype (Peirs et al, 2015). Finally, A-fibers marked by de novo expression of Neuropeptide Y (Ossipov et al, 2002b), TLR5 expression (Xu et al, 2015) or TrkB expression (Peng et al, 2017) have also been suggested to influence mechanical hypersensitivity.…”

Scaling pain threshold with microRNAs

“…Pain perception can be modulated in a variety of ways-for example, by focusing attention on the painful stimulus. On page 1168 of this issue, Peng et al (2) report that pain threshold in dorsal root ganglion neurons (DRG), which relay peripheral sensory information to the central nervous system, can be modulated by mechanisms involving a specific cluster of microRNAs (miRNAs). Remarkably, the same cluster also regulates the threshold of neuropathic pain in DRG neurons that would not be involved in pain under normal conditions.…”