Evaluation for the interaction between intrathecal melatonin and clonidine or neostigmine on formalin-induced nociception

Abstract

Aims We examined the nature of pharmacological interaction after coadministration of melatonin with clonidine or neostigmine on formalin-induced nociception at the spinal level. Further, the role of melatonin receptor subtypes in melatonin-induced antinociception was clarified. Main methods Catheters were inserted into the intrathecal space of male Sprague–Dawley rats. Pain was assessed using the formalin test (induced by a subcutaneous injection of 50 μl of a 5% formalin solution to the hindpaw). Isobolographic analysis was used for the evaluation of drug interaction between melatonin and clonidine or neostigmine. Non-selective MT 1/MT 2 receptors antagonist (luzindole), MT 2 receptor antagonist (4-P-PDOT), and MT 3 receptor/alpha-1 adrenoceptor antagonist (prazosin) were intrathecally given to verify the involvement of the melatonin receptor subtypes in the antinociception of melatonin. Furthermore, the effect of intrathecal MT 3 receptor ligand (GR 135531) was observed. Key findings Intrathecal melatonin, clonidine, and neostigmine dose-dependently suppressed the flinching response during phase 1 and phase 2 in the formalin test. Isobolographic analysis showed additivity between melatonin and clonidine or neostigmine in both phases. The antinociceptive effect of melatonin was antagonized by luzindole, 4-P-PDOT, and prazosin in the spinal cord. Intrathecal GR 135531 was ineffective against the formalin-induced flinching response. Significance These results suggest that melatonin interacts additively with clonidine and neostigmine in the formalin-induced nociception at the spinal level. Furthermore, the antinociception of melatonin is mediated through the MT 2 receptor, but not the MT 3 receptor. However, it seems that alpha-1 adrenoceptor plays in the effect of melatonin.