Targeting dorsal root ganglia and primary sensory neurons for the treatment of chronic pain: an update

Abstract

Introduction: Current treatments for chronic pain are inadequate. Here, we provide an update on the new therapeutic strategies that target dorsal root ganglia (DRGs) in the peripheral nervous system for a better and safer treatment of chronic pain.

Areas covered: Despite the complex nature of chronic pain and its underlying mechanisms, we do know that changes in the plasticity and modality of neurons in DRGs play a pivotal role. DRG neurons are heterogenous and offer potential pain targets for different therapeutic interventions. We discuss the last advancements of these interventions, which include the use of systemic and local administrations, selective nerve drug delivery, and gene therapy. In particular, we provide updates and further details on the molecular characterization of primary sensory neurons, new analgesics entering the market, and future gene therapy approaches.

Expert opinion: DRGs and primary sensory neurons are promising targets for chronic pain treatment due to their key role in pain signaling, unique anatomical location, and the potential for different targeted therapeutic interventions.

Keywords: Chronic pain; dorsal root ganglia; gene therapy; primary sensory neurons; therapeutic interventions.

Figure 1:. Administration routes to target DRGs and heterogeneity of primary sensory neurons.

(A) In chronic pain conditions, DRG neurons go through significant cellular and molecular changes that can be targeted for therapy. This can be achieved through local drug delivery methods such as peripheral nerve, intraganglionic, or intrathecal injections. Traditionally, primary sensory neurons have characterized by their morphology, electrophysiological properties and expression of unique proteins, such as parvalbumin (PVALB), neurofilament high (NFH), and peripherin (PRPH). (B) Single-cell RNAseq has revealed an additional heterogeneity of primary sensory neurons, which can be further characterized by the expression of transcripts such as parvalbumin (Pvalb), neurotrophin receptor tyrosine kinases (Ntrk2 and Ntrk3), neuropeptide somatostatin (Sst), substance P (Tac1), calcitonin gene-related peptide (Calca), and transient receptor potential cation channel 8 (Trpm8). Expression of these markers across primary sensory neuron subsets were derived from published RNA-seq data [31] (reproduced under CC-BY). (C) UMAP of Seurat-integrated DRG neurons across various species colored by DRG neuronal subtypes [23] (reproduced under CC-BY), and single-cell expression of TRPV1 in mouse and human DRG neuronal subtypes.