Differences in the sensitivity of behavioural measures of pain to the selectivity of cyclo-oxygenase inhibitors.
OBJECTIVE
Freund's complete adjuvant (FCA) is an animal model of inflammatory pain commonly used in the screening of COX-inhibitors. However, there is little understanding of how behavioural measures of the anti-inflammatory effect in the FCA model correlate to differences in mechanism of action and whether such endpoints equally reflect drug activity in humans. In the current investigation we evaluate the time course of the analgesic effect for different endpoints after treatment with drugs with varying degrees of selectivity for COX-1 and COX-2. We also assess prostaglandin (PGE(2)) and thromboxane (TXB(2)) inhibition to establish the correlation between behavioural measures and the degree of selectivity for COX-1 and COX-2.


METHODS
Sprague-Dawley rats were treated with FCA by intra-plantar injection. On post-inoculation day (PID) 7, rats received a single oral dose of naproxen, diclofenac, ketorolac or rofecoxib. Drug treatment continued until PID 21. A control group received placebo only. Behavioural endpoints for inflammatory pain and blood samples for biomarkers were obtained at various time points before and after dosing to characterise the time course of drug effect and disease progression.


RESULTS
COX-inhibitors showed no effect on the dynamic plantar test. In contrast, full analgesia was observed after drug administration for weight bearing capacity (WBC) and paw pressure (PP), with varying duration of the effect for each of the endpoints. No tolerance to drug effect was observed up to 14 days of chronic treatment. Rofecoxib showed an increase in baseline pain threshold values after chronic treatment, which may be related to its pharmacokinetic characteristics.


CONCLUSIONS
Changes in paw pressure threshold seem to best reflect the anti-hyperalgesic properties of COX-inhibitors with enough sensitivity to enable estimation of the dose-exposure-response curve.
Huntjens
Dymphy R H
DR
Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden University, Einsteinweg 55, P.O. Box 9503, 2300 RA, Leiden, The Netherlands.
Spalding
David J M
DJ
Danhof
Meindert
M
Della Pasqua
Oscar E
OE
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D015415:Biomarkers / Q000032:analysis / Q000097:blood; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000187:drug effects / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods; D023381:Endpoint Determination / Q000379:methods; D005620:Freund's Adjuvant / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D018836:Inflammation Mediators; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D010146:Pain / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology; D010147:Pain Measurement / Q000187:drug effects* / Q000379:methods*; D017288:Pain Threshold / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012680:Sensitivity and Specificity; D013929:Thromboxane B2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors
D015415:Biomarkers; D016861:Cyclooxygenase Inhibitors; D018836:Inflammation Mediators; D008565:Membrane Proteins; D013929:Thromboxane B2; D005620:Freund's Adjuvant; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496513:Ptgs1 protein, rat; C489691:Ptgs2 protein, rat; D015232:Dinoprostone