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

Abstract

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 Oprm1). 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 Oprm1 and Trpv1 expressing DRG neurons has not been precisely determined. The present study examines rat DRG neurons using high resolution multiplex fluorescent in situ hybridization to visualize molecular co-expression. Neurons positive for Trpv1 exhibited varying levels of expression for Trpv1 and co-expression of other excitatory and inhibitory ion channels or receptors. A subpopulation of densely labeled Trpv1+ neurons did not co-express Oprm1. In contrast, a population of less densely labeled Trpv1+ neurons did co-express Oprm1. This finding suggests that the medium/low Trpv1 expressing neurons represent a specific set of DRG neurons subserving the opponent processes of both transducing and inhibiting nociceptive inputs. Additionally, the medium/low Trpv1 expressing neurons co-expressed other markers implicated in pathological pain states, such as Trpa1 and Trpm8, which are involved in chemical nociception and cold allodynia, respectively, as well as Scn11a, whose mutations are implicated in familial episodic pain. Conversely, none of the Trpv1+ neurons co-expressed Spp1, 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 Trpv1 and Oprm1 coexpressing neurons may explain the remarkable efficacy of opioid drugs administered at the level of the DRG-spinal synapse, and that this subpopulation of Trpv1+ neurons is responsible for registering tissue damage.

Activation of neurons and satellite glial cells in the DRG produces morphine-induced hyperalgesia

“…Opioid receptors 11 and TLR4 [12][13][14][15] exist exclusively in small DRG neurons. We confirmed the expression of TLR4 in DRG neurons using RNA scope in situ hybridization.…”

“…Opioids activate TLR4 signaling in vitro, 9 and TLR4 mediates opioid-induced neuroinflammation in vivo. 10 In the peripheral nerve, opioid receptors 11 and TLR4 [12][13][14][15] are present in the neurons of the dorsal root ganglion (DRG). However, the precise behavior of DRG cells responsible for the development of OIH is largely unknown.…”

Ion channels in cancer-induced bone pain: from molecular mechanisms to clinical applications

“…TRPV1, also known as the capsaicin receptor, is a peripheral temperature receptor that is widely distributed in nociceptive receptors and is involved in acute and chronic inflammatory pain. It is specifically expressed in the small-and medium-sized neurons of the DRG and the first and second layers of the spinal dorsal horn ( Ma et al, 2022 ). In a rat model of Complete Freund’s adjuvant (CFA)-induced inflammatory pain, the TRPV1 expression levels in the dorsal horn of the spinal cord were significantly increased.…”

Systematic identification of potential key microRNAs and circRNAs in the dorsal root ganglia of mice with sciatic nerve injury

“…It has been well accepted that the dorsal root ganglion (DRG) plays an important role in nociceptive transmission and modulation. In particular, the DRG receives peripheral nociceptive information and transmits signaling to the central nervous system (CNS) ( Ma et al, 2022 ). Structural and functional disorders of the DRG, such as synaptic reorganization and alteration of voltage-gated sodium channels, are important for the progression of NeP.…”