Pain, 64 (1995) 323-329 323 © 1995ElsevierScienceB.V..adlrights reserved0304-3959/95/$09.50 PAIN 2910 Intraplantar injection of nerve growth factor into the rat hind paw: local edema and effects on thermal nociceptive threshold Rainer Amann *, Rufina Schuligoi, Gernot Herzeg and Josef Donnerer Department of Experimental and Clinical Pharmacology, Graz University, A-8010 Graz (Austria) (Received 16 May 1995,accepted25 May 1995) Summary Nerve growth factor (NGF) is known to produce hyperalgesia as well as to stimulate synthesis of neuropeptides in dorsal root ganglia (DRG). In the present study, we wanted to determine the effects of local NGF administration and assess to which extent mast cell-dependent factors are mediating NGF responses. Rats received 1 daily unilateral intraplantar injection for 3 days. Local edema (days 1-3), changes in thermal nociceptive threshold (days 1-4), and the content of calcitonin gene-related peptide (CGRP) and substance P (SP) in the sciatic nerve (day 4), were determined. NGF injection caused edema which was absent in rats pretreated with compound 48/80 as well as in rats treated neonatally with capsaicin ('capsaiein denervation'). NGF-induced edema was not reduced by the neurokinin-1 receptor antagonist SR140333, but attenuated by the CGRP receptor antagonist CGRP[8-37]. On each day, NGF injection caused a decrease in thermal nociceptive threshold which lasted for less than 3 h. Capsaicin denervation, but not treatment with indomethacin, abolished NGF-induced thermal hyperalgesia. Treat- ment with compound 48./80 attenuated hyperalgesia produced by the first, but not by subsequent, NGF injections. On day 4, 24 h after llhe last of 3 NGF injections, thermal nociceptive threshold was not different from control values, but at that time, CGRP and SP were elevated in the sciatic nerve. We suggest therefore that NGF-induced local edema was caused by mast cell-derived vasoactive compounds which act together with afferent neuron-derived CGRP to increase vascular permeability. NGF-induced thermal hyperalgesia most likely was caused by an increased sensitivity of peripheral endings of capsaicin sensitive afferents. This effect of NGF was not mediated by products of the cyclooxygenase pathway, and was also observed in mast cell-depleted rats. Key words: Nerve growth factor; Thermal hyperalgesia; Compound 48/80; Capsaicin; Neuropeptide Introduction Nerve growth factor (NGF) has been suggested to represent a link between inflammation and hyperalge- sia (Lewin and Mendell 1993). This view is based on the fact that in inflamed tissue, NGF concentration is increased (Weskamp anti Otten 1987; Donnerer et al. 1992; Woolf et al. 1994) and that systemic administra- tion of NGF leads to long-lasting thermal and mechan- ical hyperalgesia (Lewin et al. 1993). On primary affer- ent neurons, NGF acts on specific binding sites (Verge * Corresponding author: RainerAmann, Departmentof Experimen- tal and Clinical Pharmacology,Graz University, Univ.-Platz 4, A-8010 Graz, Austria.Tel.: (43) 316-380-4307; FAX:(43) 316-380- 4323. et al. 1989), is taken up, transported centrally (Stoeckel et al. 1975; Goedert et al. 1981), and stimulates neu- ropeptide synthesis in the DRGs (Lindsay and Harmar 1989; Vedder et al. 1993). Therefore it seems possible that increased neuropeptide synthesis leads to an in- creased availability of peptides at the spinal endings of primary afferents, which, in turn, may facilitate affer- ent transmission (cf., Urban et al. 1994). However, recently a study has been published (Woolf et al. 1994) showing that unilateral injection of NGF into the rat paw causes thermal hyperalgesia 6 h after injection. This timespan between injection of NGF and appear- ance of hyperalgesia is probably too short to allow for an effect of NGF-induced stimulation of DRG neu- ropeptide synthesis. Therefore alternative mechanisms for NGF-induced hyperalgesia are likely to be present SSDI 0304-3959(95)00120-4