The Interaction of Morphine and Adenosine Receptor Agonists on Antiallodynia in Rats with a Nerve Ligation Injury

Background: A Nerve ligation injury may produce a pain syndrome that includes tactile allodynia. Reversal effects on tactile allodynia have been demonstrated after an intrathecal administration of adenosine analogues or morphine. Adenosine receptor agonists have been known to have antinociceptive and antiallodynic effects in many animal and human studies. We examined the drug interactions between morphine and adenosine agonists in a rat model of a nerve ligation injury. Methods: Male Sprague Dawley rats were prepared with a tight ligation of the left lumbar 5 th and 6 th spinal nerves and chronic lumbar intrathecal catheter implantation for drug administration. We measured the tactile allodynia by applying von Frey filaments ipsilateral to the lesioned hindpaw. Thresholds for paw withdrawal were assessed. Morphine (1-30g), adenosine (1-30g) and R-PIA (0.1-10g) were administered to obtain the dose-response curves and the 50% effective dose (ED50). Fractions of ED50 values were administered to establish the ED50 of drug combinations. Drug interactions were evaluated by the fractional and isobolographic analyses. Allodynic thresholds for left lesioned hindpaw withdrawal to the von Frey hairs test were assessed and converted to % maximal possible effect (%MPE). Results: The antiallodynic effect of morphine, adenosine, and R-PIA were produced in a dose dependent manner. The antiallodynic effects of combinations showed a similar pattern. Isobolographic analysis revealed a synergistic interaction for the morphine-R-PIA combination but not for the morphine-adenosine combination. However, fractional analysis produced a synergistic result for two combination groups. Conclusions: The results demonstrated that intrathecal co-administration of adenosine A1 receptors agonist and morphine showed the synergistic effect on nerve ligation injury induced allodynia.