Modulation of spinal morphine analgesia and tolerance by ultra-low doses of competitive and functional opioid receptor antagonists.

摘要

Opioids traditionally produce an inhibitory effect on neuronal activity, resulting in analgesia. However, there is mounting evidence that, at extremely low doses, opioid agonists such as morphine exert excitatory effects, which can be selectively blocked by ultra-low doses of opioid receptor antagonists such as naltrexone (NTX). The excitatory actions of morphine are thought to compromise analgesia and contribute to the genesis of morphine tolerance and physical dependence. Previous studies in this laboratory have shown that ultra-low doses of NTX inhibit the development and expression of morphine tolerance. Since NTX can act at both μ and δ receptors, the present study determined the specificity of this action by using the selective μ and δ receptor antagonists, CTOP and naltrindole (NTI). The effects of a functional opioid antagonist, the adenosine A₁ receptor antagonist 8-phenyltheophylline (8-PT), on morphine action were also examined.; This study reveals that ultra-low doses of μ and δ receptor antagonists modulate morphine antinociception and tolerance through a spinal action. It is also possible to enhance morphine antinociception using ultra-low doses of an adenosine A₁ receptor antagonist. (Abstract shortened by UMI.)