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.