title: Deficits in visceral pain and hyperalgesia of mice with a disruption of the tachykinin NK1 receptor gene.
abstract: Studies in mice lacking genes encoding for substance P or its receptor (NK1), or with NK1 antagonists, have shown that this system contributes to nociception, but the data are complex. Here, we have further examined the role of NK1 receptors in pain and hyperalgesia by comparing nociceptive responses to mechanical and chemical stimulation of viscera and the resulting hyperalgesia and inflammation in NK1 knockout (-/-) and wild-type (+/+) mice. We concentrated on visceral nociception because substance P is expressed by a much greater proportion of visceral than cutaneous afferents. NK1 -/- mice showed normal responses to visceral mechanical stimuli, measured as behavioural responses to intraperitoneal acetylcholine or hypertonic saline or reflex responses to colon distension in anaesthetized mice, although -/- mice failed to encode the intensity of noxious colon distensions. In contrast, NK1 -/- mice showed profound deficits in spontaneous behavioural reactions to an acute visceral chemical stimulus (intracolonic capsaicin) and failed to develop referred hyperalgesia or tissue oedema. However, in an identical procedure, intracolonic mustard oil evoked normal spontaneous behaviour, referred hyperalgesia and oedema in -/- mice. The inflammatory effects of capsaicin were abolished by denervation of the extrinsic innervation of the colon in rats, whereas those of mustard oil were unchanged, showing that intracolonic capsaicin evokes neurogenic inflammation, but mustard oil does not. Tests of other neurogenic inflammatory stimuli in NK1 -/- mice revealed impaired behavioural responses to cyclophosphamide cystitis and no acute reflex responses or primary hyperalgesia to intracolonic acetic acid. We conclude that NK1 receptors have an essential role mediating central nociceptive and peripheral inflammatory responses to noxious stimuli that evoke neurogenic inflammation, and modulating responses to noxious mechanical stimuli. We propose that two separate hyperalgesia pathways exist, one of which is NK1 receptor dependent, whereas the other does not require intact substance P/NK1 signalling.
authors.affiliation: Department of Physiology, University of Alcalá, Alcalá de Henares, E-28871, Madrid, Spain. jennifer.laird@uah.es
authors.forename: J M
authors.initials: JM
authors.lastname: Laird
authors.forename: T
authors.initials: T
authors.lastname: Olivar
authors.forename: C
authors.initials: C
authors.lastname: Roza
authors.forename: C
authors.initials: C
authors.lastname: De Felipe
authors.forename: S P
authors.initials: SP
authors.lastname: Hunt
authors.forename: F
authors.initials: F
authors.lastname: Cervero
mesh_terms: D019342:Acetic Acid / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D002211:Capsaicin / Q000494:pharmacology; D003106:Colon / Q000187:drug effects / Q000294:innervation / Q000503:physiopathology; D003520:Cyclophosphamide / Q000494:pharmacology; D003556:Cystitis / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology; D005260:Female; D006930:Hyperalgesia / Q000139:chemically induced / Q000503:physiopathology*; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009149:Mustard Plant; D009619:Nociceptors / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D010146:Pain / Q000139:chemically induced / Q000503:physiopathology*; D010812:Physical Stimulation; D010936:Plant Extracts / Q000494:pharmacology; D010938:Plant Oils; D018040:Receptors, Neurokinin-1 / Q000235:genetics* / Q000378:metabolism; D013373:Substance P / Q000378:metabolism*; D001743:Urinary Bladder / Q000187:drug effects / Q000294:innervation / Q000503:physiopathology; D017833:Visceral Afferents / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*
chemical_list: D010936:Plant Extracts; D010938:Plant Oils; D018040:Receptors, Neurokinin-1; D013373:Substance P; D003520:Cyclophosphamide; D019342:Acetic Acid; D002211:Capsaicin; C027793:mustard oil