Meta‐chlorophenylpiperazine attenuates formalin‐induced nociceptive responses through 5‐HT 1/2 receptors in both normal and diabetic mice

1 This study was designed to investigate the effect of meta ‐chlorophenylpiperazine (m‐CPP; a 5‐hydroxytryptamine (5‐HT) receptor agonist) on the formalin‐induced nociceptive responses in normal, insulin‐dependent streptozotocin (STZ) diabetic and non‐insulin dependent genetically diabetic (db/db) mice. 2 A subcutaneous injection of diluted formalin (1% formaldehyde in 0.9% saline, 10 μ m ) under the plantar surface of the left hindpaw induced biphasic nociceptive responses, the first and second phases considered to represent acute and chronic pain, respectively. The former response in db/db mice was significantly lower than those in normal mice, and the latter responses in STZ and db/db mice were significantly lower than those in normal mice. 3 In normal mice, m‐CPP (0.32‐3.2 mg ml −1 , p.o.) exhibited potent antinociceptive activity, dose‐dependently attenuating the frst and second phase; the ID 50 value of the second phase was 0.4 mg kg −1 . m‐CPP (0.32‐3.2 mg kg −1 , p.o.) also dose‐dependently attenuated the formalin‐induced nociceptive responses in STZ‐induced diabetic mice and genetically diabetic db/db mice, and the activities were comparable to those in normal mice. 4 The antinociceptive activities of m‐CPP (1 mg kg −1 , p.o.) were significantly inhibited by pretreatment with pindolol (a 5‐HT 1 ‐receptor antagonist, 1 mg kg −1 , i.p.) or ketanserin (a 5‐HT 2 receptor antagonist, 1 mg kg −1 , i.p.) but were hardly affected by ICS205‐930 (a 5‐HT 3 receptor antagonist, 1 mg kg −1 , i.p.). 5 These results suggest that m‐CPP inhibits not only acute but also chronic pain transmission through 5‐HT 1 and 5‐HT 2 receptors, and that the 5‐hydroxytryptaminergic antinociceptive pathways are little affected by diabetes.