Sustemic physostigmine increases the antinociceptive effect of spinal morphine

In this study we evaluated the antinociceptive effect of concurrent intrathecal (i.t.) and subcutaneous (s.c.) administration of morphine and physostigmine, respectively. The experiments were performed on male Wistar rats. Intrathecal administration of morphine was performed through a catheter implanted in the subarachnoid space. The 'tail-immersion' test was used to measure animals' responses to evoked nociceptive stimuli. Interaction of drugs was analyzed using a dose addition model. Both i.t. (1-5 μg) administration of morphine and s.c. (50-250 μg/kg) administration of physostigmine increased the latencies of nociceptive responses in a dose-dependent manner. Two micrograms of i.t. morphine and 100 μg/kg of s.c. physostigmine demonstrated 31.6 ± 10.6 and 34.2 ± 11.4 percentage of maximal possible effect (%MPE), respectively. Simultaneous administration of 1 μg of i.t. morphine and 50 μg/kg of s.c. physostigmine produced a %MPE equal to 84.8 ± 16.9. Thus, bined administration of 1 μg i.t. morphine and 50 μg/kg s.c. physostigmine resulted in a strong, highly significant antinociceptive effect. This effect was much higher than the effect expected if both drugs acted in an additive manner. Supra-additive interaction observed in this study might be a result of simultaneous activation of different neurotransmitter systems involved in nociceptive processing at the spinal as well as at the supraspinal level of the CNS.