title: Systemic treatment with Mycobacterium bovis bacillus Calmette-Guérin (BCG) potentiates kinin B1 receptor agonist-induced nociception and oedema formation in the formalin test in mice.
abstract: This study investigates the effect and some of the mechanisms involved following systemic treatment of mice with Mycobacterium bovis bacillus Calmette-Guérin (BCG) (1 dose per animal containing 6.4 x 10(4) colony-forming units (CFu) 20-60 days beforehand) on modulation of the kinin B1 receptor agonist-induced nociception and oedema formation in the formalin test. Intraplantar (i.p.l.) co-injection of des-Arg9-bradykinin (4-32 nmol/paw) or des-Arg10-kallidin (1-15 nmol/paw), together with sub-maximal concentrations of formalin (0.01 or 0.5%), potentiated (P < 0.01) both pain phases and the paw oedema caused by formalin in animals pre-treated with saline. However, when animals were pre-treated with BCG, the dose-response curves for both B1 agonists were shifted 2 to 8-fold to the left. These B1-mediated effects peaked at 30-45 days after BCG treatment and were still elevated at 60 days after BCG injection. The pain response and oedema formation caused by i.p.l. co-injection of des-Arg9-bradykinin, together with formalin in BCG-pre-treated animals, were dose-dependently antagonised by i.p.l. co-injection of the B1 antagonist des-Arg9[Leu8]bradykinin (1-15 nmol/paw), but were not affected by the B2 antagonist Hoe 140 (10 nmol/paw). The i.p.l. co-injection of tyrosine8-bradykinin (a B2 agonist, 3-15 nmol/paw) with formalin (0.01 or 0.5%) potentiated the pain response and paw oedema in BCG and saline-pre-treated animals to the same extent (P < 0.01). The actions caused by tyrosine8-bradykinin were antagonised by Hoe 140, while des- Arg9[Leu8]bradykinin (10 nmol/paw) had no effect. Dexamethasone (0.5 mg/kg, s.c.), given every 24 h, from day 0 to 30-45, inhibited significantly the potentiation of nociceptive response and oedema formation caused by i.p.l. co-injection of formalin plus des-Arg9-bradykinin, while indomethacin (2 mg/kg, i.p.) or phenidone (30 mg/kg, i.p.), given 1 h prior, caused less inhibition. These data show that the long-term systemic treatment of mice with BCG produced dose-related potentiation of B1 receptor agonist-mediated nociception and oedema formation, without affecting similar responses caused by the B2 receptor agonist tyrosine8-bradykinin. Thus, systemic treatment of mice with BCG induces upregulation of B1 receptors, without affecting B2-mediated responses, by a mechanism that seems to be secondary to cytokine release.
authors.affiliation: Department of Pharmacology, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, Brazil.
authors.forename: R O
authors.initials: RO
authors.lastname: de Campos
authors.forename: M G
authors.initials: MG
authors.lastname: Henriques
authors.forename: J B
authors.initials: JB
authors.lastname: Calixto
mesh_terms: D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004487:Edema / Q000139:chemically induced / Q000503:physiopathology*; D005557:Formaldehyde / Q000494:pharmacology; D006614:Hindlimb; D007213:Indomethacin / Q000494:pharmacology; D007609:Kallidin / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D051379:Mice; D009163:Mycobacterium bovis / Q000276:immunology*; D010146:Pain / Q000139:chemically induced / Q000503:physiopathology*; D010147:Pain Measurement / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology; D043783:Receptor, Bradykinin B1; D018002:Receptors, Bradykinin / Q000819:agonists / Q000502:physiology*
chemical_list: D011720:Pyrazoles; D043783:Receptor, Bradykinin B1; D018002:Receptors, Bradykinin; C026201:bradykinin, Tyr-; C024626:bradykinin, des-Arg(9)-; D005557:Formaldehyde; D007609:Kallidin; C051090:bradykinin, Leu(8)-des-Arg(9)-; C052787:kallidin, des-Arg(10)-; C065679:icatibant; D003907:Dexamethasone; C015429:phenidone; D001920:Bradykinin; D007213:Indomethacin