Adenosine receptor subtype-selective antagonists in inflammation and hyperalgesia.
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.
Bilkei-Gorzo
Andras
A
Institute of Molecular Psychiatry, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany. abilkei@uni-bonn.de
Abo-Salem
Osama M
OM
Hayallah
Alaa M
AM
Michel
Kerstin
K
Müller
Christa E
CE
Zimmer
Andreas
A
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004487:Edema / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D006930:Hyperalgesia / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D015394:Molecular Structure; D010146:Pain / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D021122:Protein Subunits; D058915:Purinergic P1 Receptor Antagonists; D013329:Structure-Activity Relationship
D000894:Anti-Inflammatory Agents, Non-Steroidal; D021122:Protein Subunits; D058915:Purinergic P1 Receptor Antagonists