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

Abstract

Currently the treatment of chronic pain is inadequate and compromised by debilitating central nervous system side effects. Here we discuss 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: The DRGs contain the cell bodies of primary sensory neurons including nociceptive neurons. After painful injuries, primary sensory neurons demonstrate maladaptive molecular changes in DRG cell bodies and in their axons. These changes result in hypersensitivity and hyperexcitability of sensory neurons (peripheral sensitization) and are crucial for the onset and maintenance of chronic pain. We discuss the following new strategies to target DRGs and primary sensory neurons as a means of alleviating chronic pain and minimizing side effects: inhibition of sensory neuron-expressing ion channels such as TRPA1, TRPV1, and Nav1.7, selective blockade of C- and Aβ-afferent fibers, gene therapy, and implantation of bone marrow stem cells. Expert opinion: These peripheral pharmacological treatments, as well as gene and cell therapies, aimed at DRG tissues and primary sensory neurons can offer better and safer treatments for inflammatory, neuropathic, cancer, and other chronic pain states.

Keywords: Chronic pain; dorsal root ganglia; pain therapy; sensory neurons.

Figure 1

Morphological, electrophysiological, and molecular studies have supported the specificity theory that different populations of DRG neurons are responsible for distinct sensory modalities. Noxious stimuli, including mechanical, chemical, and thermal noxious stimuli, are sensed by nociceptors, characterized by the expression of the neurofilament peripherin (Prph), voltage-gated sodium channels Nav1.8 and Nav1.9, as well as transient receptor potential cation channels Trpv1 and Trpa1. Low threshold mechanical stimuli such as light touch activate mechanoreceptors that specifically expressed neurofilament high (Nfh) and toll-like receptor 5 (Tlr5). Another type of DRG neuron is the proprioceptor that senses movement or vibration and it is generally characterized by the expression of parvalbumin (Pvalb).Information from DRG neuron subtypes arrives into different regions of the spinal cord and then is transmitted to the brain where the different stimuli are ultimately decoded. In chronic pain conditions DRG neurons undergo major cellular and molecular changes, which can be therapeutically targeted by using local drug delivery such as by peripheral nerve, intraganglionic, or intrathecal injections.