The role of sensory nerve endings in nerve growth factor-induced airway hyperresponsiveness to histamine in guinea-pigs.
1. Nerve growth factor induces an airway hyperresponsiveness in vivo in guinea-pigs, as we have shown previously. Since antagonizing the neurokinin-1 (NK(1)) receptor can prevent this NGF-induced airway hyperresponsiveness and since sensory nerves release tachykinins, we investigated the role of sensory nerves in the NGF-induced airway hyperresponsiveness. 2. We used isolated tracheal rings from guinea-pigs to measure tracheal contractility. In these rings sensory nerve endings are present, but these endings lack any contact with their cell bodies. 3. In this in vitro system, NGF dose-dependently induced a tracheal hyperresponsiveness to histamine. The NK(1) receptor antagonist SR140333 could block the induction of tracheal hyperresponsiveness. 4. To further investigate the involvement of sensory nerve endings we used the cannabinoid receptor 1 (CB(1)) agonist R-methanandamide to inhibit excitatory events at the nerve terminal. The CB(1) receptor agonist was capable of blocking the tracheal hyperresponsiveness to NGF in the isolated system, as well as the airway hyperresponsiveness to NGF in vivo. 5. This indicates that NGF can induce an increase in airway responsiveness in the absence of sensory nerve cell bodies. NGF may act by increasing substance P release from sensory nerve endings, without upregulation of substance P in the neurons. Substance P in its turn is responsible for the induction of the NGF-induced airway hyperresponsiveness.
de Vries
A
A
Department of Pharmacology and Pathophysiology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, P.O. Box 80082, 3508 TB Utrecht, The Netherlands.
van Rijnsoever
C
C
Engels
F
F
Henricks
P A
PA
Nijkamp
F P
FP
D000403:Airway Resistance / Q000187:drug effects*; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D020932:Nerve Growth Factor / Q000494:pharmacology*; D011984:Sensory Receptor Cells / Q000502:physiology*; D014132:Trachea / Q000187:drug effects* / Q000294:innervation / Q000502:physiology
D001095:Arachidonic Acids; C088155:methanandamide; D006632:Histamine; D020932:Nerve Growth Factor