Interaction between Neostigmine and Morphine in the Neuropathic Pain Model

Hwang, Jai Hyun; Kim, Young Kook; Han, Sung Min; Lee, Dong Myung

Abstract

BACKGROUND: Spinally administered neostigmine, but not morphine, has been well known to reverse the mechanical allodynia in human and animal studies. The efficacy of morphine in neuropathic pain state is somewhat controversial. Using an isobolographic analysis, we examine the spinal interaction between neostigmine and morphine in a rat model of neuropathic pain.
METHODS
Male Sprague Dawley rats were prepared with tight ligation of left lumbar 5th and 6th spinal nerves and chronic lumbar intrathecal catheter. Intrathecal dose response curves were established for the antiallodynic effect of neostigmine (0.3, 1.0, 3.0, and 10 microgram) and morphine (0.3, 1.0, 3.0, and 10 microgram) alone to obtain the ED50 for each agent. ED50 fractions (1/2, 1/4, 1/8, and 1/16) of drug combination of neostigmine-morphine were administered. Allodynic thresholds for left hindpaw withdrawal to von Frey hairs application were assessed and converted to %MPE. The ED50 of neostigmine-morphine combinations was established and isobolographic analysis of the drug interaction was carried out.
RESULTS
Intrathecal neostigmine and morphine alone produced dose-dependent reductions of tactile allodynia. ED50 values are 0.43 microgram (0.21~0.86 microgram) for neostigmine and 0.39 microgram (0.07~2.01 microgram) for morphine. The log dose responses were plotted from the peak effect of %MPE in each group of neostigmine and morphine. The experimental ED50 1.34E-2 microgram (2.1E-4-0.85 microgram) for neostigmine and morphine combination was found to be significantly below the theoretical additive ED50 value 0.41 microgram (P<0.05).
CONCLUSION
The results suggest that intrathecal neostigmine and morphine alone produce a dose dependent antagonism on touch evoked allodynia and intrathecal neostigmine is synergistic at the spinal level when combined with intrathecal morphine in a rat model of neuropathy.