PERIPHERAL AND CENTRAL MECHANISMS OF NGF-INDUCED HYPERALGESIA

Mechanisms underlying the hyperalgesia induced by a single systemic in jection of nerve growth factor (NGF) in adult rats were studied in viv o. A single dose of NGF initiated a prolonged thermal hyperalgesia to a radiant heat source within minutes that lasted for days. Animals whi ch had been pretreated with the mast cell degranulating compound 48/80 or either one of two specific 5-hydroxytryptamine receptor antagonist s (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 hypera lgesia was reversed and the animals responded with an initial hypoalge sia to the thermal stimuli. Whereas these results indicate a periphera l 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 antagonis t MK-801. in contrast to the almost immediate thermal hyperalgesia fol lowing a single injection of NGF, a significant mechanical hyperalgesi a began only after a 7 h latency. This NGF-induced mechanical hyperalg esia was not blocked by any of the treatments that attenuated the ther mal 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-indu ced inflammation) may be involved in the development of thermal hypera lgesia, since it could be blocked by concomitant treatment with anti-N GF antisera. These data indicate that NGF-induced thermal and mechanic al hyperalgesia are mediated by different mechanisms. The rapid onset component of thermal hyperalgesia is due to a peripheral mechanism inv olving the degranulation of mast cells, whereas the late component inv olves central NMDA receptors. In contrast, the NGF-induced mechanical hyperalgesia seems to be independent of mast cell degranulation or cen tral NMDA receptor sites.