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Opioid Tolerance Development: A Pharmacokinetic/Pharmacodynamic Perspective

  • Therapeutic Tolerance: Pharmacokinetic-Pharmacodynamic Mechanisms
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Abstract

The opioids are commonly used to treat acute and severe pain. Long-term opioid administration eventually reaches a dose ceiling that is attributable to the rapid onset of analgesic tolerance coupled with the slow development of tolerance to the untoward side effects of respiratory depression, nausea and decreased gastrointestinal motility. The need for effective-long term analgesia remains. In order to develop new therapeutics and novel strategies for use of current analgesics, the processes that mediate tolerance must be understood. This review highlights potential pharmacokinetic (changes in metabolite production, metabolizing enzyme expression, and transporter function) and pharmacodynamic (receptor type, location and functionality; alterations in signaling pathways and cross-tolerance) aspects of opioid tolerance development, and presents several pharmacodynamic modeling strategies that have been used to characterize time-dependent attenuation of opioid analgesia.

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Abbreviations

AC:

adenylyl cyclase

BBB:

blood brain barrier

CREB:

cAMP-responsive element binding protein

CYP:

cytochrome P450

DOR:

δ-opioid receptor

GABA:

γ-amino-butyric acid

Glu:

glutamate

GPCR:

G-protein coupled receptor

GRK:

G-protein receptor kinase

hPXR:

human pregnane X receptor

KOR:

κ-opioid receptor

K p,brain :

brain-to-serum ratio

l-Arg:

l-arginine

l-Cit:

l-citrulline

M3G:

morphine-3-glucuronide

M6G:

morphine-6-glucuronide

NMDA:

N-methyl-d-aspartate

nNOS:

neuronal nitric oxide synthase

NR:

NMDA receptor

OR:

opioid receptors

PD:

pharmacodynamic

P-gp:

P-glycoprotein

PK:

pharmacokinetic

PKA:

protein kinase A

PSD-95:

post-synaptic density complex

sGC:

soluble guanylyl cyclase

SNP:

single nucleotide polymorphism

UGT:

uridine-5′-diphosphate-glucuronosyltranserase

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Acknowledgements

This work was supported by National Institutes of Health Grant R01 GM61191. E.R.O. was supported by a predoctoral fellowship from GlaxoSmithKline.

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  1. Division of Pharmacotherapy and Experimental Therapeutics, School of Pharmacy, The University of North Carolina at Chapel Hill, CB #7360, Kerr Hall 2311, Chapel Hill, NC, 27599-7360, USA

    Emily O. Dumas & Gary M. Pollack

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Correspondence to Emily O. Dumas.

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Guest Editors: Kathleen M. K. Boje and Gary M. Pollack

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Dumas, E.O., Pollack, G.M. Opioid Tolerance Development: A Pharmacokinetic/Pharmacodynamic Perspective. AAPS J 10, 537–551 (2008). https://doi.org/10.1208/s12248-008-9056-1

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