Targeting neurotrophic factors: Novel approaches to musculoskeletal pain

Abstract

Chronic pain represents a substantial unmet medical need globally. In recent years, the quest for a new generation of novel, safe, mechanism-based analgesic treatments has focused on neurotrophic factors, a large group of secreted proteins that control the growth and survival of different populations of neurons, but that postnatally are involved in the genesis and maintenance of pain, with biological activity in both the periphery and the central nervous system. In this narrative review, we discuss the two families of neurotrophic proteins that have been extensively studied for their role in pain: first, the neurotrophins, nerve growth factor (NGF) and brain-derived growth factor (BDNF), and secondly, the GDNF family of ligands (GFLs). We provide an overview of the pain pathway, and the pain-producing effects of these different proteins. We summarize accumulating preclinical and clinical findings with a focus on musculoskeletal pain, and on osteoarthritis in particular, because the musculoskeletal system is the most prevalent source of chronic pain and of disability, and clinical testing of these novel agents - often biologics- is most advanced in this area.

Keywords: Nerve growth factor; Neurotrophins; Osteoarthritis; Pain; Trk.

Fig. 1.. Neuroanatomy of the pain pathway and sites of action of the different neurotrophic factors under investigation as targets for chronic musculoskeletal pain.

Sensory neurons, including nociceptors (medium sized Aδ-fibers and small unmyelinated slow-conducting C-fibers) innervate peripheral tissues. Nociceptors are equipped with a broad array of specialized receptors and channels to detect noxious signals in the innervated tissues and carry them to the dorsal horn (DH) of the spinal cord. To perform this function, nociceptors have a unique pseudo-unipolar morphology, with an axonal stalk that extends from the cell body in the dorsal root ganglia (DRG) and splits into two terminals. The peripheral terminal innervates the tissues, and the central terminal extends into the DH to synapse with second-order neurons. Injury or inflammation in the innervated tissues results in release of mediators by resident (damaged) tissue cells and infiltrating inflammatory cells (for example macrophages, mast cells), causing peripheral sensitization. At the same time, gene expression changes occur in the DRG, and inflammatory cells infiltrate the DRG. Ongoing nociceptive input from the periphery results in increased excitability of second order neurons in the spinal cord [16]. Neurotrophic factors can act at different sites to modify pain processing pathways (mostly to increase excitability and promote pain). Nerve growth factor (NGF), secreted by cells in the innervated tissues, is active in the periphery and binds TrkA expressed by afferents, resulting in sensitization. The NGF-TrkA complex can be internalized by neurons and retrogradely transported to cell bodies in the DRG, initiating gene expression changes that lead to synthesis of pro-algesic peptides and ion channels. Pain-producing effects of brain-derived neurotrophic factor (BDNF), which binds TrkB, have been documented in the periphery and in the dorsal horn. Members of the GDNF family of ligands (GFL) are active in the periphery as well as in the central nervous system, but their signaling in musculoskeletal pain and in the joint has been less studied.