Beta adrenergic inhibition of capsaicin-induced, NK1 receptor-mediated nerve growth factor biosynthesis in rat skin.
Excitation of primary afferent neurons stimulates the expression of cytokines and nerve growth factor (NGF) in innervated tissues. Since NGF is a neurotrophic and immunomodulatory factor contributing to inflammatory hyperalgesia and tissue response to injury, this study was conducted in order to investigate the mechanisms by which afferent neuron stimulation by topical application of capsaicin increases NGF in the rat skin. Thereby it was sought to identify possible targets for pharmacological modulation of NGF biosynthesis. Topical capsaicin (>1 mg/ml ethanol) caused a concentration- and time-dependent increase in the concentration of NGF in rat skin. The capsaicin-induced increase of NGF was not significantly affected by indomethacin administered at a dose (2 mg/kg) that abolishes prostaglandin E2 biosynthesis. The NGF increase was suppressed by treatment of rats with the selective tachykinin NK1 receptor antagonist SR140333 (0.1 mg/kg), and by the beta adrenergic agonist terbutaline (0.3 mg/kg). The effect of terbutaline was reversed by the beta adrenergic antagonist propranolol (1 mg/kg). Terbutaline also inhibited the increase in NGF caused by intraplantar injection of the NK1 receptor agonist substance P (SP), but did not significantly affect that caused by carrageenan. The results show that topical administration of capsaicin causes a primarily NK1 receptor-dependent increase in the NGF content of rat skin, which is susceptible to inhibition by beta adrenergic agonists. These observations not only suggest regulation of skin NGF biosynthesis by afferent neuronal and adrenergic mechanisms, but also indicate possible targets for pharmacological modulation of skin NGF biosynthesis.
Amann
Rainer
R
Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitätplatz 4, A-8010 Graz, Austria. rainer.amann@meduni-graz.at
Schuligoi
Rufina
R
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D002211:Capsaicin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008297:Male; D020932:Nerve Growth Factor / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D018040:Receptors, Neurokinin-1 / Q000378:metabolism*; D012867:Skin / Q000187:drug effects / Q000378:metabolism*
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D011943:Receptors, Adrenergic, beta; D018040:Receptors, Neurokinin-1; D020932:Nerve Growth Factor; D002211:Capsaicin