Pharmacokinetic/pharmacodynamic modelling of the anti-hyperalgesic and anti-nociceptive effect of adenosine A1 receptor partial agonists in neuropathic pain

Eur J Pharmacol. 2005 May 9;514(2-3):131-40. doi: 10.1016/j.ejphar.2005.03.026.


The objective of this investigation was to characterise the pharmacokinetic-pharmacodynamic correlation of adenosine A1 receptor partial agonists in the chronic constriction injury model of neuropathic pain. Following intravenous administration of 8-methylamino-N6-cyclopentyl-adenosine (MCPA; 10 mg/kg) and 2'deoxyribose-N6-cyclopentyl-adenosine (2'dCPA; 20 mg/kg), the time course of the effect on the mechanical paw pressure threshold was determined in conjunction with plasma concentrations. Population pharmacokinetic/pharmacodynamic analysis was applied to derive individual concentration-effect relationships. A composite model consisting of an E(max) model for the anti-hyperalgesic effect in combination with a linear model for the anti-nociceptive effect accurately described the concentration-effect relationship. For both compounds, a full anti-hyperalgesic effect was observed. The values of the EC50 for the anti-hyperalgesic effect were (mean+/-S.D.): 3170+/-1460 and 2660+/-1200 ng/ml for MCPA and 2'dCPA versus 178+/-51 ng/ml for the reference full agonist 5'deoxyribose-N6-cyclopentyl-adenosine (5'dCPA). The values of the slope for the anti-nociceptive effect were 1.9+/-0.30 and 1.2+/-0.20 g.microl/ng, respectively, versus 55+/-8 g microl/ng for 5'dCPA. Adenosine A1 receptor partial agonists behave as full agonists with regard to the anti-hyperalgesic effect in neuropathic pain, but the anti-nociceptive effect is diminished.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / blood
  • Adenosine / pharmacokinetics
  • Adenosine / pharmacology
  • Adenosine A1 Receptor Agonists*
  • Algorithms
  • Analgesics / pharmacokinetics*
  • Analgesics / pharmacology
  • Analysis of Variance
  • Animals
  • Behavior, Animal / drug effects
  • Deoxyadenosines / blood
  • Deoxyadenosines / pharmacokinetics
  • Deoxyadenosines / pharmacology
  • Hyperalgesia / prevention & control*
  • Injections, Intravenous
  • Male
  • Neuralgia / prevention & control*
  • Rats
  • Time Factors


  • 2'-deoxyribose-N6-cyclopentyladenosine
  • 8-methylamino-N6-cyclopentyladenosine
  • Adenosine A1 Receptor Agonists
  • Analgesics
  • Deoxyadenosines
  • Adenosine