Ligand-biased activation of extracellular signal-regulated kinase 1/2 leads to differences in opioid induced antinociception and tolerance.
Opioids produce antinociception by activation of G protein signaling linked to the mu-opioid receptor (MOPr). However, opioid binding to the MOPr also activates β-arrestin signaling. Opioids such as DAMGO and fentanyl differ in their relative efficacy for activation of these signaling cascades, but the behavioral consequences of this differential signaling are not known. The purpose of this study was to evaluate the behavioral significance of G protein and internalization dependent signaling within ventrolateral periaqueductal gray (vlPAG). Antinociception induced by microinjecting DAMGO into the vlPAG was attenuated by blocking Gαi/o protein signaling with administration of pertussis toxin (PTX), preventing internalization with administration of dynamin dominant-negative inhibitory peptide (dyn-DN) or direct inhibition of ERK1/2 with administration of the MEK inhibitor, U0126. In contrast, the antinociceptive effect of microinjecting fentanyl into the vlPAG was not altered by administration of PTX or U0126, and was enhanced by administration of dyn-DN. Microinjection of DAMGO, but not fentanyl, into the vlPAG induced phosphorylation of ERK1/2, which was blocked by inhibiting receptor internalization with administration of dyn-DN, but not by inhibition of Gαi/o proteins. ERK1/2 inhibition also prevented the development and expression of tolerance to repeated DAMGO microinjections, but had no effect on fentanyl tolerance. These data reveal that ERK1/2 activation following MOPr internalization contributes to the antinociceptive effect of some (e.g., DAMGO), but not all opioids (e.g., fentanyl) despite the known similarities for these agonists to induce β-arrestin recruitment and internalization.
Washington State University, Department of Psychology, 14204 NE Salmon Creek Ave, Vancouver, WA 98686, United States. Electronic address: erin.bobeck@mssm.edu.
Erin N
EN
Bobeck
Oregon Health & Science University, Department of Neurological Surgery, 3181 SW Sam Jackson Park Road, Portland, OR 97239, United States.
Susan L
SL
Ingram
Oregon Health & Science University, Department of Physiology and Pharmacology, 3181 SW Sam Jackson Park Road, Portland, OR 97239, United States.
Sam M
SM
Hermes
Oregon Health & Science University, Department of Physiology and Pharmacology, 3181 SW Sam Jackson Park Road, Portland, OR 97239, United States.
Sue A
SA
Aicher
Washington State University, Department of Psychology, 14204 NE Salmon Creek Ave, Vancouver, WA 98686, United States.
Michael M
MM
Morgan
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D004361:Drug Tolerance / Q000502:physiology*; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005283:Fentanyl / Q000494:pharmacology; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D059226:Nociceptive Pain / Q000188:drug therapy* / Q000201:enzymology*; D010487:Periaqueductal Gray / Q000187:drug effects / Q000201:enzymology; D017207:Rats, Sprague-Dawley
D000701:Analgesics, Opioid; D002070:Butadienes; D004791:Enzyme Inhibitors; D009570:Nitriles; C113580:U 0126; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D005283:Fentanyl
Analgesia; ERK1/2; Functional selectivity; Periaqueductal gray