The frequency of firing in nociceptive neurons signals the signals the intensity of pain, and pro-inflammatory mediators such as prostaglandin E2 (PGE2) enhance the sensation of pain by increasing the frequency of action potential firing in response to a given level of painful stimulus. One hypothesis to explain the increase proposes that the threshold for action potential initiation is lowered because the activation curve of a nociceptor-specific voltage-activated Na current, NaV1.8, is shifted to more negative values by PGE2 (Akopian et al., 1996; England et al., 1996), but we have found that the action potential threshold in fact changes little when AP firing is accelerated by PGE2 (Momin et al., 2008). The enhanced firing is, however, abolished by a blocker of the Ih inward current activated by hyperpolarisation. The voltage sensitivity of Ih shifts in the positive direction in small nociceptive neurons (but not in large neurons) when pro-inflammatory mediators such as PGE2 increase levels of cAMP. By this mechanism the inward current between the resting membrane potential and the threshold for firing of action potentials is enhanced, and the rate of depolarisation in the interval between action potentials is therefore increased. We conclude that Ih is a major mechanism responsible for increasing the frequency of action potential firing following tissue damage or metabolic stress. Genetic deletion of HCN1 ablates the fast-activating Ih which is seen in large neurons and in a small sub-population of cold-sensitive neurons, but leaves unaffected the slowly-activating Ih seen in small nociceptive neurons. Deletion of HCN2, on the other hand, reduces Ih in small neurons; the remaining current is insensitive to cAMP and probably reflects expression of the cAMP-insensitive HCN3. Significantly, deletion of HCN2 abolishes the effect of PGE2 in accelerating action potential discharge. In behavioural experiments using the formalin injection test the Ih blocker ZD7844 effectively blocked the late phase of pain behaviour, thought to be due to release of pro-inflammatory mediators. We are currently investigating the contribution of HCN isoforms to pain behaviour in vivo.