The present study was aimed to investigate the peripheral effects of chlorpheniramine and ranitidine and their relationship with cholinergic system on the somatic pain in rats. The somatic pain was induced by using formalin test. The effects of H1 and H2 receptor antagonists, chlorpheniramine and ranitidine, respectively, on formalininduced pain was studied in rats. Physostigmine and atropine were subcutaneously injected alone and also in combination with chlorpheniramine and ranitidine. Formalin 1% produced biphasic pain response. Chlorpheniramine and ranitidine significantly reduced the second phase of pain (p<0.05). Physostigmine at doses 0.4mg/kg significantly reduced the second phase of pain. Atropine (2 mg/kg) had no significant effect in the first and second phases. Pre-treatment of chlorpheniramine (20mg/kg) before physostigmine (0.4mg/kg) prevented physostigmine induced antinociception. Ranitidine (40mg/kg) before physostigmine (0.4mg/kg) significantly suppressed the antinociceptive effects of physostigmine. Atropine before chlorpheniramine and ranitidine reversed the analgesic effects of chlorpheniramine and ranitidine. These results indicate that physostigmine has been able to inhibit the somatic pain through the cholinergic muscarinic receptors. Both of the histamine H1 and H2 receptor antagonists have analgesic effects and histamine H2 but not H1 antagonist probably is involved in the analgesic effects induced by physostigmine.