Abstract
Alterations in brain opioid binding and opioid pharmacodynamics following chronic (8-day) naltrexone (NTX) treatment were determined in pertussis toxin (PTX)-treated mice. Intrathecal (IT) and intracerebroventricular (ICV) PTX produced a time-dependent, long-lasting inhibition of morphine (SC) analgesia without modifying basal nociception. Inhibition was maximal 16 days following PTX treatment, and was still observed at 40 days. Relative to placebo controls, NTX treatment produced supersensitivity to morphine analgesia in all control mice and in mice pretreated with PTX 1 day before NTX. Supersensitivity was not observed in 7-day PTX-pretreated mice. [ 3H]D-Ala 2-D-Leu 5]enkephalin ([ 3H]DADLE) and [ 3H][D-Ala 2-MePhe 4-Gly(ol) 5]enkephalin ([ 3H]DAMGO) binding sites were increased by NTX treatment in saline- and PTX-pretreated groups. K Ds were unchanged. These results indicate that PTX does not alter opioid antagonist-induced receptor upregulation. However, PTX treatment can diminish morphine potency in upregulated and control mice. Therefore, opioid analgesia in control and upregulated mice appears to be mediated by receptors linked to a common PTX-sensitive G-protein. Furthermore, in 7-day PTX-pretreated mice, NTX increased binding sites without altering morphine potency, which suggests that new binding sites can appear without being functionally coupled.
Published Version
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