Antinociceptive Effects of Intrathecal Morphine and NMDA Receptor Antagonists, MK 801 and CPP, on the Formalin Test in Rats

Leem, Jeong Gill; Shin, Kwang Il

Abstract

BACKGROUND: It is emphasized that repetitive stimulation of small diameter afferent fibers produces a progressive increase in the action potential discharge and a prolonged increase in the excitability of neurons in the spinal cord following the stimulus and that this facilitatory component has a unique pharmacology. To investigate the behavioral parallels of this spinal facilitation, we evalusted the antinociceptive effects of intrathecal morphine, N-methyl-D-aspartate(NMDA), (+)-5-methyl-10,11- dihydro-5H-dibizo(a,d) cycloheptene-5, 10-imine hydrogen maleate(MK801) and (+/-)-3-(2-carboxy- piperazine-4-yl)-propyl-I-phosphonic acid(CPP), on the formalin test in rats.
METHODS
Four to six days after chronic lumbar intrathecal catheterization, normal saline, morphine(0.1 to 30 ug), MK801(0.1 to 10 ug), CPP(0.1 to 5 ug) or NMDA(10 or 100 ng) were administered intrathecally before formalin injection. Spontanesous flinches were observed at 1-2 and 5-6 min(phase 1) and at 10 min intervals thereafter for 50 min(phase 2) after subcutaneous formalin injection into the dorsum of the right hind paw for each drug treated rats.
RESULTS
Intrathecal morphine produced dose dependent inhibition of the phase 1 and phase 2 response(ED50=0.63 ug and 0.37 ug, respectively). Intrathecal MK801(0.1 to 10 ug) and CPP(0.1 to 5 ug) inhibited the phase 2 response more strongly than phase 1 response and inhibition of the phase 2 response(P<0.05 at any dose) was dose dependent(ED50=0.54 ug for MK801 and 0.15 ug for CPP). 1ntrathecal NMDA(10 or 100 ng) produced augmented responses in the intermediate and phase 2(P<0.05), but had no effect on the phase 1 response(P>0.7). Relative potencies of MK801 and CPP when compared with morphine were 1.34 and 0.41, respectively.
CONCLUSIONS
This study suggests that intrathecal morphine and NMDA receptor antagonist(MK801 and CPP) have an antinociceptive effect on pathological pain mediated by central sensitization and that NMDA receptor antagonists can be utilized selectively in the treatment of components of central sensitization.