Purposes: The alpha 2 (α(2))-adrenoceptor is highly important in the antinociception of tramadol administered systemically and intrathecally. However, it is unclear whether tramadol at the spinal level exerts an antinociceptive effect by directly binding with α(2)-adrenoceptors in the spinal cord. This study was conducted to investigate the relationship between α(2)-adrenoceptors and the antinociception of tramadol at the spinal level.
Methods: The rat formalin test was designed to determine whether the intrathecal α(2)-adrenoceptor antagonist yohimbine could reverse the antinociceptive effect of intrathecal tramadol. The binding affinity of tramadol for α(2)-adrenoceptors in the spinal cord was determined by radioligand binding assay using the labeled α(2)-adrenoceptor antagonist [(3)H]-yohimbine.
Results: The nociceptive test showed that intrathecal tramadol induced significant antinociception whereas pretreatment with intrathecal yohimbine partially reversed this antinociception. Scatchard analysis of the binding data showed [(3)H]-yohimbine had high affinity (K(d) = 1.79 nM: ) for the α(2)-adrenoceptor in the rat spinal cord, and that tramadol inhibited specific binding of [(3)H]-yohimbine with the spinal cord membranes with a high affinity constant (K(i) = 34.14 μM: ) and an IC50 of 68.25 μM: , which indicated that tramadol was much less potent than [(3)H]-yohimbine at binding with α(2)-adrenoceptors of the spinal cord.
Conclusion: The results suggested that, with very weak binding affinity for α(2)-adrenoceptors, the antinociception of intrathecal tramadol is partially related to α(2)-adrenoceptors, and its intrathecal antinociception may mainly involve its indirect activation of α(2)-adrenoceptors in the spinal cord.