Regulation of Wring frequency in nociceptive neurons by pro-inXammatory mediators

Nociceptive neurons generate trains of action potentials in response to painful stimuli, and the frequency of Wring signals the intensity of the pain. Pro-inXammatory mediators such as prostaglandin E2 (PGE2) enhance the sensation of pain by increasing the frequency of action potential Wring in response to a given level of painful stimulus. The mechanism by which the Wring frequency is enhanced is discussed in the present review. One hypothesis proposes that the threshold for action potential initiation is lowered because the activation curve of a nociceptor-speciWc voltage-activated Na current, NaV1.8, is shifted to more negative values by PGE2. Recent measurements in our lab show, however, that the action potential threshold in fact changes little when AP Wring is accelerated by PGE2. The enhanced Wring is, however, abolished by a blocker of an inward current activated by hyperpolarisation, called Ih. The voltage sensitivity of Ih shifts in the positive direction in small nociceptive neurons when they are exposed to proinXammatory mediators, such as PGE2, which activate adenylate cyclase and therefore increase levels of cAMP. By this mechanism the inward current between the resting membrane potential and the threshold for Wring of action potentials is enhanced, and the rate of depolarisation in the interval between action potentials is therefore increased. We conclude that the major mechanism responsible for increasing action potential Wring following tissue damage or metabolic stress is the hyperpolarisation-activated inward current, Ih, and that other mechanisms play at most a minor role.