Chronic morphine treatment decreases the Cav1.3 subunit of the L-type calcium channel.
Voltage-gated L- and N-type calcium channels (VOCs) are implicated in the activity of morphine, but their contribution to the expression of opioid tolerance remains uncertain. L- and N-type VOCs are heteropentamers of alpha(1), alpha(2)delta, beta, and gamma subunits. The alpha(1) subunit forms both the ion pore and the binding site for ligands. The Ca(v)1.2 and Ca(v)1.3 are the neuronal dihydropyridine (DHP)-sensitive L-type channel subunit types. The Ca(v)2.2 subunit is found in omega conotoxin GVIA-sensitive N-type calcium channels. Ca(v)1.2 VOC gating properties are phosphorylation-dependent with many kinases implicated. We hypothesized that changes in channel subunit structure or phosphorylation state, induced by chronic opioid exposure, may in part explain changes in calcium regulation observed both in vivo and in vitro. Antibodies, specific for the Ca(v)1.2, Ca(v)1.3, and Ca(v)2.2 subunits of VOCs were employed with Western immunoassays to access whether chronic morphine treatment had an effect on receptor protein levels. The L-type channel Ca(v)1.3 protein, but not the Ca(v)1.2 protein or phosphorylation state, significantly decreased upon chronic morphine treatment. The Ca(v)2.2 subunit protein of the N-type channel of VOCs remained unchanged. The Ca(v)1.3 subunit modification may represent one of many potential adaptive changes in tolerance to morphine-induced changes in intracellular calcium.
Haller
Victoria L
VL
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia 23298-0524, USA. vhaller@vcu.edu
Bernstein
Marissa A
MA
Welch
Sandra P
SP
D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D020864:Calcium Channels, N-Type / Q000187:drug effects; D015536:Down-Regulation; D004361:Drug Tolerance; D007279:Injections, Subcutaneous; D008297:Male; D008636:Mesencephalon / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D008970:Molecular Weight; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D010766:Phosphorylation; D021122:Protein Subunits; D013997:Time Factors
D000701:Analgesics, Opioid; C514350:CACNA1C protein, mouse; C500963:Cacna1b protein, mouse; C485995:Cacna1d protein, mouse; D020746:Calcium Channels, L-Type; D020864:Calcium Channels, N-Type; D021122:Protein Subunits; D009020:Morphine; D002118:Calcium