AUTHOR=Ma Wenting , Sapio Matthew R. , Manalo Allison P. , Maric Dragan , Dougherty Mary Kate , Goto Taichi , Mannes Andrew J. , Iadarola Michael J. 

TITLE=Anatomical Analysis of Transient Potential Vanilloid Receptor 1 (Trpv1+) and Mu-Opioid Receptor (Oprm1+) Co-expression in Rat Dorsal Root Ganglion Neurons

JOURNAL=Frontiers in Molecular Neuroscience

VOLUME=15

YEAR=2022

URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2022.926596

DOI=10.3389/fnmol.2022.926596

ISSN=1662-5099

ABSTRACT=<p>Primary afferent neurons of the dorsal root ganglia (DRG) transduce peripheral nociceptive signals and transmit them to the spinal cord. These neurons also mediate analgesic control of the nociceptive inputs, particularly through the μ-opioid receptor (encoded by <italic>Oprm1</italic>). While opioid receptors are found throughout the neuraxis and in the spinal cord tissue itself, intrathecal administration of μ-opioid agonists also acts directly on nociceptive nerve terminals in the dorsal spinal cord resulting in marked analgesia. Additionally, selective chemoaxotomy of cells expressing the TRPV1 channel, a nonselective calcium-permeable ion channel that transduces thermal and inflammatory pain, yields profound pain relief in rats, canines, and humans. However, the relationship between <italic>Oprm1</italic> and <italic>Trpv1</italic> expressing DRG neurons has not been precisely determined. The present study examines rat DRG neurons using high resolution multiplex fluorescent <italic>in situ</italic> hybridization to visualize molecular co-expression. Neurons positive for <italic>Trpv1</italic> exhibited varying levels of expression for <italic>Trpv1</italic> and co-expression of other excitatory and inhibitory ion channels or receptors. A subpopulation of densely labeled <italic>Trpv1</italic>+ neurons did not co-express <italic>Oprm1</italic>. In contrast, a population of less densely labeled <italic>Trpv1</italic>+ neurons did co-express <italic>Oprm1</italic>. This finding suggests that the medium/low <italic>Trpv1</italic> expressing neurons represent a specific set of DRG neurons subserving the opponent processes of both transducing and inhibiting nociceptive inputs. Additionally, the medium/low <italic>Trpv1</italic> expressing neurons co-expressed other markers implicated in pathological pain states, such as <italic>Trpa1</italic> and <italic>Trpm8</italic>, which are involved in chemical nociception and cold allodynia, respectively, as well as <italic>Scn11a</italic>, whose mutations are implicated in familial episodic pain. Conversely, none of the <italic>Trpv1</italic>+ neurons co-expressed <italic>Spp1</italic>, which codes for osteopontin, a marker for large diameter proprioceptive neurons, validating that nociception and proprioception are governed by separate neuronal populations. Our findings support the hypothesis that the population of <italic>Trpv1</italic> and <italic>Oprm1</italic> coexpressing neurons may explain the remarkable efficacy of opioid drugs administered at the level of the DRG-spinal synapse, and that this subpopulation of <italic>Trpv1</italic>+ neurons is responsible for registering tissue damage.</p>