John J. Bonica Award Lecture: Peripheral neuronal hyperexcitability: the "low-hanging" target for safe therapeutic strategies in neuropathic pain.

Abstract

Neuropathic pain (NP) resulting from injury or disease of the somatosensory system is a common, debilitating chronic disorder that significantly undermines quality of life. Preclinical and clinical studies have considerably advanced our understanding of the myriad peripheral and central changes in neuronal and non-neuronal cells associated with persistent pain states. Disappointingly, advances in clinical therapies for NP have not paralleled the substantial advances in basic science. Most drugs currently used for the treatment of NP bind to receptors that are widely expressed in the peripheral and central nervous systems, and hence are frequently associated with adverse effects. Therefore, identifying key targets involved in the initiation and maintenance of NP in the periphery, with guidance from meticulous clinical evidence, merits renewed focus. We consider the relative importance of peripheral and central mechanisms and present several lines of clinical and preclinical evidence supporting the tenet that spontaneous and ectopic activity in primary afferent neurons plays a critical role in NP. Several potential peripheral “pain generator” sites have been identified, and defining their role in NP states of different etiologies is important for targeted therapy. Hyperexcitability of peripheral neurons may represent a “low-hanging target” in the development of safe therapies for a subset of patients with NP. We summarize work from our group and others that identifies potential peripheral drug targets, including peripheral opioid receptors, involved in the modulation of NP. In future drug development efforts, therapies directed at peripheral mechanisms may offer potential advantages over current CNS-penetrating drugs, including minimal adverse effects.