An analysis of drug interaction between morphine and neostigmine in rats with nerve-ligation injury

Intrathecal neostigmine reverses mechanical allodynia in humans and animals . The efficacy of morphine in a neuropathic pain state is still controversi al. This study examines the antiallodynic interaction between morphine and neostigmine in a rat model of neuropathic pain. Rats were prepared with tig ht ligation of left L5-6 (fifth and sixth lumbar) spinal nerves and chronic intrathecal catheter implantation. Mechanical allodynia was measured by us ing application of von Frey hairs to the left hindpaw. Morphine (1, 3, 10, and 30 mu g) and neostigmine (0.3, 1, 3, and 10 mu g) were administered int rathecally to obtain the dose-response curves and the 50% effective dose (E D50) 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 establi sh the ED50. Isobolographic and fractional analyses for the drug interactio n were performed. Intrathecal morphine produced a moderate antagonism of th e tactile allodynia. A morphine-neostigmine combination produced a dose-dep endent increase in withdrawal threshold of the lesioned hind paw with reduc ed side effects. Both analyses revealed a synergistic interaction after the coadministration of morphine and neostigmine. These experiments suggest th at the antiallodynic action of a morphine-neostigmine combination is synerg istic at the spinal level. Implications: This study indicates that by using both isobolographic and fractional analyses, the antiallodynic effect of i ntrathecal morphine and neostigmine is synergistic when coadministered intr athecally. In a rat model of neuropathic pain, the intrathecal morphine pro duced a moderate antagonism on touch-evoked allodynia at the spinal level.