Update on peripheral mechanisms of pain: beyond prostaglandins and cytokines

Abstract

The peripheral nociceptor is an important target of pain therapy because many pathological conditions such as inflammation excite and sensitize peripheral nociceptors. Numerous ion channels and receptors for inflammatory mediators were identified in nociceptors that are involved in neuronal excitation and sensitization, and new targets, beyond prostaglandins and cytokines, emerged for pain therapy. This review addresses mechanisms of nociception and focuses on molecules that are currently favored as new targets in drug development or that are already targeted by new compounds at the stage of clinical trials--namely the transient receptor potential V1 receptor, nerve growth factor, and voltage-gated sodium channels--or both.

Figure 1

Schematic drawing of a sensory ending of a nociceptor in the tissue. The membrane at the bottom shows ion channels for transduction (which produce a sensor potential, SP), a voltage-gated Na⁺ channel for the generation of action potentials (APs), and voltage-gated K⁺ and Ca²⁺ channels that control excitability. The other part of the membrane displays receptors for mediators that act on different second messenger systems. Classical inflammatory mediators are bradykinin, prostaglandin E₂, 5-hydroxytryptamine, and histamine. ASIC, acid-sensing ion channel; PTX, purinergic ion channel; TRP, transient receptor potential.