Mechanisms underlying the hyperalgesia induced by a single systemic injection of nerve growth factor (NGF) in adult rats were studied in vivo. A single dose of NGF initiated a prolonged thermal hyperalgesia to a radiant heat source within minutes that lasted for days. Animals which had been pretreated with the mast cell degranulating compound 48/80 or either one of two specific 5‐hydroxytryptamine receptor antagonists (ICS 205–930 and methiothepin) also developed an NGF‐induced thermal hyperalgesia, but onset was delayed by more than 3 h. In the presence of ICS 205‐930 or methiothepin the early component NGF‐induced hyperalgesia was reversed and the animals responded with an initial hypoalgesia to the thermal stimuli. Whereas these results indicate a peripheral mechanism for the initial thermal hyperalgesia, the later phase (7 h–4 days after NGF) appeared to be centrally maintained, since it could be selectively blocked by the non‐competitive NMDA receptor antagonist MK‐801. In contrast to the almost immediate thermal hyperalgesia following a single injection of NGF, a significant mechanical hyperalgesia began only after a 7 h latency. This NGF‐induced mechanical hyperalgesia was not blocked by any of the treatments that attenuated the thermal hyperalgesia, indicating that a separate mechanism may be involved. Additional electrophysiological experiments showed that NGF‐induced hyperalgesia was not maintained by an increased amount of spontaneous activity in C‐fibres. A final result showed that endogenous release of NGF in a model of acute inflammation (complete Freund's adjuvant‐induced inflammation) may be involved in the development of thermal hyperalgesia, since it could be blocked by concomitant treatment with anti‐NGF antisera. These data indicate that NGF‐induced thermal and mechanical hyperalgesia are mediated by different mechanisms. The rapid onset component of thermal hyperalgesia is due to a peripheral mechanism involving the degranulation of mast cells, whereas the late component involves central NMDA receptors. In contrast, the NGF‐induced mechanical hyperalgesia seems to be independent of mast cell degranulation or central NMDA receptor sites.