Characteristics of Tolerance to Somatic and Visceral Antinociception After Continuous Epidural Infusion of Morphine in Rats

Abstract

A continuous epidural infusion of morphine may cause a complicated tolerance to develop, depending on the spinal and supraspinal sites. We designed this study to clarify the characteristics of the tolerance to somatic and visceral antinociception after epidural morphine infusion. Rats received epidural infusion of morphine at the rates of 50 or 100 microg kg(-1) h(-1), or isotonic sodium chloride solution for 7 days. The tail-flick (TF) test and colorectal distension (CD) test were used to measure the somatic and visceral antinociceptive effects, respectively. Nociceptive tests were performed on Days 1, 2, 3, 4, and 7. After 7 days, time-response curves after epidural morphine (10 microg) or intraperitoneal morphine (3 mg) challenge tests were conducted to assess the magnitude of tolerance. Epidurally infused morphine significantly increased percent maximal possible effects (%MPEs) (P < 0.05) in both the TF and CD tests, depending on the concentration of morphine. In the epidural morphine challenge test, increases in %MPEs were significantly attenuated (P < 0.05) in the morphine-infused group compared with the isotonic sodium chloride solution-infused group. The increases in %MPEs in the intraperitoneal challenge test were also attenuated in the morphine-infused group. We conclude that morphine tolerance to both somatic and visceral antinociception develops rapidly during epidural infusion and is based on the development of tolerance at the systemic, as well as the epidural, level. A continuous epidural infusion of morphine rapidly induces tolerance to visceral and somatic antinociception in rats. This development is based on the development of tolerance at the systemic, as well as the epidural, level.