Neurotrophins, Cytokines, and Pain

The neurotrophin and cytokine families of proteins regulate neuronal functions that affect survival, growth, and differentiation. Because of their extensive expression throughout the nervous system, some neurotrophins and cytokines are widely accepted to modulate synaptic plasticity and nociceptive processing. Among the neurotrophin family are nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin 3 (NT-3), which all bind to the tyrosine receptor kinases. The potential for BDNF as a therapeutic target is supported by a large body of evidence demonstrating its role in driving plastic changes in nociceptive pathways to initiate and maintain chronic pain. On the other hand, NGF has already proved fruitful as an analgesic target, with efficacy shown for NGF-neutralizing antibodies for pain relief in rheumatic diseases. The cytokine family includes the interleukins, tumor necrosis factors (TNFs), chemokines, interferons (IFNs), and transforming growth factor ß (TGF-ß) family. These bind, often promiscuously, to the heterogeneous group of cytokine receptors, and this cytokine signaling is essential for normal responses of the innate and adaptive immune systems. In pathophysiological states, chronic inflammation enhances the expression of pro-inflammatory cytokines, and many studies support a modulatory role of cytokines in nociceptive processes. At the forefront of anticytokine therapy for analgesia are TNF and IL6 monoclonal antibodies, which are licensed treatments for pain relief in rheumatoid arthritis. This article reviews the pro- and antinociceptive roles of key members of the neurotrophin and cytokine families in the context of chronic pain mechanisms and therapeutic approaches.