Opioid inhibition and desensitization of calcium channel currents in rat dorsal root ganglion neurons.
The mu-opioid [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO) inhibited the high voltage-activated calcium channel currents of neonatal rat dorsal root ganglion neurons in a voltage-dependent manner. The low voltage-activated currents were not affected by DAMGO. The inhibitory effect was eliminated by pretreatment of the cell with pertussis toxin, indicating that the receptor was coupled with the pertussis toxin-sensitive G protein. Although the DAMGO inhibition occurred quickly, it was relieved gradually during the 5-min application of DAMGO. The recovery from desensitization after washout of DAMGO was very slow. Pretreatment of the cell with 1 microM DAMGO for 18 hr induced almost complete tolerance to the agonist. GTP-gamma-S also inhibited the high voltage-activated calcium channel currents mimicking DAMGO inhibition and the inhibition diminished during continuous application, suggesting that desensitization could occur without receptor stimulation by the agonist. Baclofen caused a similar inhibition and desensitization to those by DAMGO, and the inhibition by the subsequently applied DAMGO was attenuated. Thus, desensitization by these distinct receptor agonists is heterologous. Modulation of G proteins which are coupled with these agonists may be involved in the desensitization process.
Nomura
K
K
Department of Pharmacology, Northwestern University Medical School, Chicago, Illinois.
Reuveny
E
E
Narahashi
T
T
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D002121:Calcium Channel Blockers; D017868:Cyclic AMP-Dependent Protein Kinases / Q000187:drug effects; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins / Q000494:pharmacology*; D005727:Ganglia, Spinal / Q000187:drug effects*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects*; D011493:Protein Kinase C / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
D000700:Analgesics; D002121:Calcium Channel Blockers; D004745:Enkephalins; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D001418:Baclofen