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Involvement of endogenous nitric oxide in the mechanism of bradykinin‐induced peripheral hyperalgesia
Author(s) -
Nakamura Akihiro,
Fujita Manabu,
Shiomi Hirohito
Publication year - 1996
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1996.tb15205.x
Subject(s) - hyperalgesia , bradykinin , chemistry , sodium nitroprusside , nitric oxide , pharmacology , endocrinology , medicine , omega n methylarginine , arginine , nitric oxide synthase , nociception , biochemistry , receptor , amino acid , organic chemistry
1 When N G ‐nitro‐L‐arginine methyl ester (L‐NAME, 0.1–10 nmol) or N G ‐monomethyl‐L‐arginine (L‐NMMA, 10 nmol‐1 μmol) was intradermally administered with bradykinin (BK, 3 nmol) into the instep of rat hind‐paws, a dose‐related suppression of BK‐induced hyperalgesia, assessed by the paw‐pressure test, was produced. 2 L‐Arginine (1 μmol) but not D‐arginine (1 μmol) reversed the suppressive effects of L‐NAME (10 nmol) and L‐NMMA (1 μmol) on BK‐induced hyperalgesia. 3 Concomitant intradermal administration of BK (3 nmol) with haemoglobin (1 nmol) significantly suppressed BK‐induced hyperalgesia in the paw‐pressure test. The BK‐induced hyperalgesia was abolished by concomitant intradermal administration of either a guanylate cyclase inhibitor, methylene blue (10 nmol), or LY83583 (1 nmol). In addition, KT5823 (1 nmol) or R p ‐8‐bromoguanosine‐3′:5′‐cyclic monophosphothioate (R p ‐8‐Br‐cGMPS; 1 nmol), an inhibitor of cyclic GMP‐dependent protein kinase, also significantly suppressed BK‐induced hyperalgesia. 4 The carrageenin‐induced hyperalgesia was significantly attenuated by L‐NAME in a dose‐dependent manner. 5 L‐Arginine (1 μmol), sodium nitroprusside (1 μmol), dibutyryl cyclic GMP (1 μmol) or 8‐bromo cyclic GMP (1 μmol) all failed to produce any significant relieving effect on the nociceptive threshold of rodent hind‐paws. Concomitant administrations of each agent with a sub‐threshold dose (0.1 nmol) of BK induced significant hyperalgesia. 6 R p ‐adenosine 3′:5′‐cyclic monophosphothioate (R p ‐cAMPS; 1 nmol), an inhibitor of cyclic AMP‐dependent protein kinase, significantly suppressed BK‐induced mechanical hyperalgesia. Concomitant administration of forskolin (1 nmol) with 8‐bromo cyclic GMP (100 nmol) induced significant hyperalgesia. 7 In the superfusion experiment of a blister base on the instep of rodent hind‐paws, intradermally administered BK (3 nmol) significantly increased the outflow of both cyclic GMP and cyclic AMP from the blister base. Concomitant administrations of L‐NAME (10 nmol) with BK significantly reduced the BK‐induced outflow of cyclic GMP without affecting the cyclic AMP content. 8 These results suggest that the NO‐cyclic GMP pathway is involved in the mechanism of BK‐induced hyperalgesia, and an activation of both cyclic GMP‐and cyclic AMP‐second messenger system plays an important role in the production of peripherally induced mechanical hyperalgesia.