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Studies suggest that acute and chronic opioids can regulate the cAMP‐dependent protein kinase (PKA) signaling pathway and that changes in this pathway may be involved in opioid tolerance. In the present study, we examined the role of cAMP‐PKA on μ‐opioid receptor downregulation and tolerance in mice. Mice were injected intracerebroventricular (i.c.v.) and intrathecal (i.t.) once a day with an antisense oligodeoxynucleotide directed at the mRNA for the α catalytic subunit of mouse PKA. Controls were treated with saline or a mismatch oligodeoxynucleotide. On day 2 of treatment, mice were implanted s.c. with a 25‐mg morphine pellet and an osmotic minipump infusing morphine (40 mg/kg/day) for 3 days. Other mice were implanted with an osmotic minipump infusing etorphine (125, 250 μg/kg/day) for 2 days. Control mice were implanted s.c. with inert placebo pellets. At the end of treatment, pumps and pellets were removed and mice tested for morphine or etorphine analgesia. Other mice were sacrificed and μ‐opioid receptor binding assays conducted in whole brain. Both infusion doses of etorphine produced significant tolerance (ED50 shift = 3.6 and 6.3‐fold). The higher etorphine infusion produced downregulation of μ‐receptor density (≈30%) while the lower infusion dose of etorphine did not. Morphine treatment also produced significant tolerance in mice (ED50 shift = 4.5‐fold), but no receptor downregulation. Antisense to PKA partially blocked tolerance induced by the higher dose of etorphine, but had no effect on receptor downregulation. On the other hand, antisense to PKA completely blocked tolerance induced by morphine and the lower infusion dose of etorphine. The mismatch oligodeoxynucleotide had no effect on any measure. These results suggest that PKA has a limited role in opioid agonist‐induced receptor downregulation. However, the partial block of tolerance for the high infusion dose of etorphine and the complete block of tolerance for morphine and the low infusion dose of etorphine suggests that PKA may play a critical role in tolerance that is “receptor‐regulation‐independent.” Synapse 38:322–327, 2000. © 2000 Wiley‐Liss, Inc.

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