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REGIONAL ANESTHESIA AND PAIN MEDICINE

The Effects of Intrathecal Morphine Encapsulated in L- and D-Dipalmitoylphosphatidyl Choline Liposomes on Acute Nociception in Rats

Tomoki Nishiyama, MD, PhD^*,, Rodney J. Y. Ho, PhD, Danny D. Shen, PhD^,§, and Tony L. Yaksh, PhD^*

*Department of Anesthesiology, University of California, San Diego, California; Department of Anesthesiology, the University of Tokyo, Faculty of Medicine, Tokyo, Japan; Department of Pharmaceutics, University of Washington; and §Pain Research, Clinical Division, Fred Hutchinson Cancer Research Center, Seattle, Washington

Address correspondence and reprint requests to Tomoki Nishiyama, MD, PhD, 3-2-6-603, Kawaguchi, Kawaguchi-shi, Saitama, 332-0015, Japan.

Liposomes can serve as a sustained-release carrier system, permitting the spinal delivery of large opioid doses restricting the dose for acute systemic uptake. We evaluated the antinociceptive effects of morphine encapsulated in liposomes of two isomeric phospholipids, L-dipalmitoylphosphatidyl choline (L-DPPC) and D-dipalmitoylphosphatidyl choline (D-DPPC), in comparison with morphine in saline. Sprague-Dawley rats with chronic lumbar intrathecal catheters were tested for their acute nociceptive response using a hindpaw thermal escape test. Their general behavior, motor function, pinna reflex, and corneal reflex were also examined. The duration of antinociception was longer in both liposomal morphine groups than in the free morphine group. The peak antinociceptive effects were observed within 30 min after intrathecal morphine, L-DPPC or D-DPPC morphine injection. The rank order of the area under the effect-time curve for antinociception was L-DPPC morphine > D-DPPC morphine > morphine. The 50% effective dose was: 2.7 µg (morphine), 4.6 µg (L-DPPC morphine), and 6.4 µg (D-DPPC morphine). D-DPPC morphine had less side effects for a given antinociceptive AUC than morphine. In conclusion, L-DPPC and D-DPPC liposome encapsulation of morphine prolonged the antinociceptive effect on acute thermal stimulation and could decrease side effects, compared with morphine alone.

Implications: Two isomers of liposome (L-dipalmitoylphosphatidyl choline and D-dipalmitoylphosphatidyl choline) encapsulation of morphine prolonged the analgesic effect on acute thermal-induced pain when administered intrathecally and could decrease side effects, compared with morphine alone.