An Analysis of Drug Interaction Between Morphine and Neostigmine in Rats with Nerve-Ligation Injury

Abstract

Intrathecal neostigmine reverses mechanical allodynia in humans and animals. The efficacy of morphine in a neuropathic pain state is still controversial. This study examines the antiallodynic interaction between morphine and neostigmine in a rat model of neuropathic pain. Rats were prepared with tight ligation of left L5–6 (fifth and sixth lumbar) spinal nerves and chronic intrathecal catheter implantation. Mechanical allodynia was measured by using application of von Frey hairs to the left hindpaw. Morphine (1, 3, 10, and 30 μg) and neostigmine (0.3, 1, 3, and 10 μg) were administered intrathecally to obtain the dose-response curves and the 50% effective dose (ED50) for each drug. ED50 values and fractions of the ED50 values (1/2, 1/4, and 1/8) were administered intrathecally in an equal dose ratio to establish the ED50. Isobolographic and fractional analyses for the drug interaction were performed. Intrathecal morphine produced a moderate antagonism of the tactile allodynia. A morphine-neostigmine combination produced a dose-dependent increase in withdrawal threshold of the lesioned hind paw with reduced side effects. Both analyses revealed a synergistic interaction after the coadministration of morphine and neostigmine. These experiments suggest that the antiallodynic action of a morphine-neostigmine combination is synergistic at the spinal level. Implications This study indicates that, by using both isobolographic and fractional analyses, the antiallodynic effect of intrathecal morphine and neostigmine is synergistic when coadministered intrathecally. In a rat model of neuropathic pain, the intrathecal morphine produced a moderate antagonism on touch-evoked allodynia at the spinal level.