Evidence for adenosine- and serotonin-mediated antihyperalgesic effects of cizolirtine in rats suffering from diabetic neuropathy.
Cizolirtine is a novel non-opioid drug which demonstrated antinociceptive activity in numerous pain models in rodents. Yet, its mechanism of action remains unknown. Several lines of evidence support the idea that adenosine (ADO) and serotonin (5-HT) modulate nociceptive signaling. Our study aimed at investigating whether these neuroactive molecules could be implicated in the mechanism of action of cizolirtine. Cizolirtine-induced antihyperalgesia was compared before and after pretreatment with ADO A(1)-A(2A) and 5-HT(1B/1D) receptor ligands in rats rendered diabetic by streptozotocin pretreatment and suffering from neuropathic pain. Cizolirtine alone (30-80 mg/kg, i.p.) significantly increased mechanical nociceptive thresholds. Acute pretreatment with the A(1)-A(2A) receptor antagonist caffeine (5 mg/kg, i.p.) or the 5-HT(1B/1D) receptor antagonist GR-127,935 (3 mg/kg, i.p.) significantly reduced the antihyperalgesic effects of cizolirtine. Conversely, cizolirtine-induced antihyperalgesia was promoted by pretreatment with either the selective A(1) receptor agonist CPA (0.3 mg/kg, i.p.) or the selective 5-HT(1B) receptor agonist CP-94,253 (3mg/kg, i.p.), and this potentiation was totally prevented by acute pretreatment with respective antagonists. Interestingly, A(1) receptor blockade by DPCPX inhibited the promoting effect of CP-94,253 on cizolirtine-induced antihyperalgesia, suggesting that the adenosine A(1)-mediated step takes place downstream the serotonin 5-HT(1B)-mediated step in the neurobiological mechanisms underlying cizolirtine action.
Aubel
Bertrand
B
INSERM, U677, and Université Pierre et Marie Curie-Paris6, Faculté de Médecine Pierre et Marie Curie, Site Pitié-Salpétrière, UMR S677, 91 Boulevard de l'Hôpital, Paris F-75013, France.
Kayser
Valérie
V
Farré
Antonio
A
Hamon
Michel
M
Bourgoin
Sylvie
S
D000241:Adenosine / Q000037:antagonists & inhibitors / Q000502:physiology*; D000700:Analgesics / Q000627:therapeutic use*; D000818:Animals; D019540:Area Under Curve; D002110:Caffeine / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental; D003928:Diabetic Nephropathies / Q000139:chemically induced / Q000150:complications; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006930:Hyperalgesia / Q000188:drug therapy* / Q000209:etiology; D008297:Male; D010069:Oxadiazoles / Q000494:pharmacology; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D011597:Psychomotor Performance / Q000187:drug effects; D011720:Pyrazoles / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D014828:Vocalization, Animal / Q000187:drug effects
D000700:Analgesics; D010069:Oxadiazoles; D010879:Piperazines; D011720:Pyrazoles; D012702:Serotonin Antagonists; C090701:GR 127935; D012701:Serotonin; D002110:Caffeine; D000241:Adenosine; C075798:cizolirtine