Dorsal root ganglion neurons and tyrosine hydroxylase--an intriguing association with implications for sensation and pain

Abstract

Tyrosine hydroxylase (TH) is a rate-limiting enzyme broadly expressed in noradrenergic and dopaminergic neurons in the central nervous system [57,70]. TH is also expressed by peripheral sympathetic neurons [98] as well as by enteric neurons within the gut [81,84]. Over 30 years ago, TH was unexpectedly discovered in developing and adult rodent cranial and dorsal root ganglion (DRG) neurons. Today, TH-expressing DRG neurons are being re-discovered as a relevant subpopulation. This review addresses the emerging importance of TH-expressing DRG neurons in sensation and pain mechanisms, focusing specifically on: 1) their nature as C-low threshold mechanoreceptors (C-LTMRs); 2) their involvement in nociception/pain; and 3) their catecholaminergic phenotype.

Figure 1. Morphological features of TH-expressing DRG neurons (quantitative and qualitative data in B, C is based on mouse)

(A) Adult TH-expressing DRG neurons have been detected in a number of species, including rat, guinea pig and mouse (—, not determined; * in humans, only embryonic expression has so far been studied [43]). (B) TH-expressing mouse DRG neurons are primarily small and medium-sized. Interestingly, differences can be observed when comparing visceral and non-visceral neurons, the former being represented by both small and medium-sized neurons, while the latter most often are small in size [data summarized from [7,10] and pooled to show differences between subpopulations. Percentage refers to the distribution among neuronal soma sizes of the total number of neurons measured for each target tissue/organ (921 non-visceral; 35 colonic and 74 urinary bladder)]. (C) On average, 15% of mouse DRG neurons express TH, although variations between DRGs innervating visceral versus non-visceral tissues or glabrous versus hairy skin are observed. Micrographs show examples of TH- and CGRP-expressing DRG neurons innervating non-visceral or visceral tissues, and the patterns of coexpression between the two markers. (Upper micrograph; L4-5 DRG neurons) TH-expressing DRG neurons (in green) innervating non-visceral tissues very seldom coexpress CGRP (in blue), and only rarely the two markers can be detected in the same neuron (double arrowhead). (Lower micrograph; S1 DRG neurons; in red, neurons innervating the urinary bladder) TH-expressing DRG neurons innervating the urinary bladder often coexpress CGRP (arrows). Additional bladder-projecting DRG neurons expressing CGRP but lacking TH are observed (arrowheads). Finally, several TH- (in green) or CGRP-only (in red) neurons are detected in the S1 DRG, and again a rare TH/CGRP coexpressing neurons (double arrowhead) Scale bar: 50 μm, applies for both micrographs.

Figure 2. Neurochemical features of TH-expressing DRG neurons

(A) Neurochemical expression in DRG somata of unidentified L4-5 DRG neurons (not identified to tissue of innervation), and those innervating hairy skin or viscera ( , present; , absent; —, not determined). TH-expressing DRG neurons exhibit distinctive neurochemical features, some of which appear to be dependent on target (e.g., compare CGRP expression between neurons innervating hairy skin and viscera). Although VGLUT2 expression remains to be confirmed in somata of TH-expressing DRG neurons projecting to hairy skin and viscera (δ), the presence of the transporter in nerve terminals in close apposition to hair follicles [8], and the fact that virtually all visceral DRG neurons express VGLUT2 [11,12], suggest that TH-expressing DRG neurons synthesize both VGLUT2 and VGLUT3. (B) The presence of enzymes associated with catecholamine synthesis and metabolism, including TH and associated molecules (NET-1), supports the existence of dopaminergic (1) or noradrenergic (2) phenotypes for TH-expressing DRG neurons (shading denotes enzymes and catecholamines present or secreted from DRG somata). Abbreviations: Cav3.2, T-type calcium channel Cav.3.2; Gfrα2, GDNF family receptor alpha-2; MRGPRs, mas related G-protein coupled receptors; NaV1.8/9, voltage gated sodium channel 1.8/9; NFH, neurofilament high; NtsR1, neurotensin receptor type 1; P2X3, P2X purinoceptor 3; Piezo2, Piezo-type mechanosensitive ion channel component 2; RET, rearranged in transformation proto-oncogene; SP, substance P; TAFA4, chemokine-like protein TAFA4; TrkA, Tropomyosin receptor kinase A; TRPA1, Transient receptor potential cation channel, member A1; VGLUT, vesicular glutamate transporter type; Y2R, neuropeptide tyrosine receptor, type 2.