Involvement of endogenous nitric oxide in the mechanism of bradykinin-induced peripheral hyperalgesia.

Abstract

1. When NG-nitro-L-arginine methyl ester (L-NAME, 0.1-10 nmol) or NG-monomethyl-L-arginine (L-NMMA, 10 nmol-1 mumol) 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 mumol) but not D-arginine (1 mumol) reversed the suppressive effects of L-NAME (10 nmol) and L-NMMA (1 mumol) 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 Rp-8-bromoguanosine-3':5'-cyclic monophosphothioate (Rp-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 mumol), sodium nitroprusside (1 mumol), dibutyryl cyclic GMP (1 mumol) or 8-bromo cyclic GMP (1 mumol) 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. Rp-adenosine 3':5'-cyclic monophosphothioate (Rp-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.

• Authors: A Nakamura, M Fujita, H Shiomi
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 117 Issue 3 Pg. 407-412 (Feb 1996) ISSN: 0007-1188 [Print] England
• PMID: 8821527 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Nitric Oxide
• Carrageenan
• Cyclic AMP
• Nitric Oxide Synthase
• Cyclic GMP
• Bradykinin
• NG-Nitroarginine Methyl Ester

Topics

• Animals
• Blister (metabolism)
• Bradykinin
• Carrageenan
• Cyclic AMP (metabolism, physiology)
• Cyclic GMP (metabolism, physiology)
• Enzyme Inhibitors (pharmacology)
• Hyperalgesia (chemically induced, metabolism)
• Male
• NG-Nitroarginine Methyl Ester (pharmacology)
• Nitric Oxide (metabolism, physiology)
• Nitric Oxide Synthase (antagonists & inhibitors)
• Pain Threshold (drug effects)
• Rats
• Rats, Sprague-Dawley