Adenosine receptor subtype-selective antagonists in inflammation and hyperalgesia

• Published in: Naunyn-Schmiedeberg's archives of pharmacology 2008-03, Vol.377 (1), p.65-76
• Main Authors: Bilkei-Gorzo, Andras, Abo-Salem, Osama M., Hayallah, Alaa M., Michel, Kerstin, Müller, Christa E., Zimmer, Andreas
• Format: Article
• Language: English
• Subjects: Animals; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Anti-Inflammatory Agents, Non-Steroidal - therapeutic use; Biomedical and Life Sciences; Biomedicine; Disease Models, Animal; Edema - drug therapy; Edema - immunology; Edema - metabolism; Hyperalgesia - drug therapy; Hyperalgesia - immunology; Hyperalgesia - metabolism; Male; Mice; Mice, Inbred Strains; Molecular Structure; Neurosciences; Original Article; Pain - drug therapy; Pain - immunology; Pain - metabolism; Pharmacology/Toxicology; Protein Subunits; Purinergic P1 Receptor Antagonists; Structure-Activity Relationship
• ISSN: 0028-1298; 1432-1912
• DOI: 10.1007/s00210-007-0252-9

In this study, we examined the effects of systemic and local administration of the subtype-selective adenosine receptor antagonists PSB-36, PSB-1115, MSX-3, and PSB-10 on inflammation and inflammatory hyperalgesia. Pharmacological blockade of adenosine receptor subtypes after systemic application of antagonists generally led to a decreased edema formation after formalin injection and, with the exception of A 3 receptor antagonism, also after the carrageenan injection. The selective A 2B receptor antagonist PSB-1115 showed a biphasic, dose-dependent effect in the carrageenan test, increasing edema formation at lower doses and reducing it at a high dose. A 1 and A 2B antagonists diminished pain-related behaviors in the first phase of the formalin test, while the second, inflammatory phase was attenuated by A 2B and A 3 antagonists. The A 2B antagonist was particularly potent in reducing inflammatory pain dose-dependently reaching the maximum effect at a low dose of 3 mg/kg. Inflammatory hyperalgesia was totally eliminated by the A 2A antagonist MSX-3 at a dose of 10 mg/kg. In contrast to the A 1 antagonist, the selective antagonists of A 2A , A 2B , and A 3 receptors were also active upon local administration. Our results demonstrate that the blockade of adenosine receptor subtypes can decrease the magnitude of inflammatory responses. Selective A 2A antagonists may be useful for the treatment of inflammatory hyperalgesia, while A 2B antagonists have potential as analgesic drugs for the treatment of inflammatory pain.