Cyclooxygenases (COX), and their products the prostaglandins, are important in inflammation and inflammatory nociception. COX-1 is found in primary afferent neurons that are thought to be nociceptive, and COX inhibitors alter neuronal processing of noxious inputs. We have used knockout mice to study COX-1 in inflammation and nociceptive processing.
Wild type (WT, n = 12) or COX-1 knockout (KO, n = 12) mice were injected intradermally with 100 µl of Freund’s Complete Adjuvant (FCA, 2.5 µg/µl M. tub. in mineral oil) at two sites around the left tibiotarsal joint under brief inhalational anaesthesia (4 % halothane in O2). Mice were monitored for 20 days for paw swelling, mechanical allodynia using von Frey filaments, and thermal hyperalgesia. Animals were humanely killed by cervical dislocation on day 20. Paw circumferences and changes in nociceptive behaviour were compared to pre-injection values by ANOVA followed by Dunnett’s or Bonferroni tests. Values given are means ± S.E.M.
All animals showed a rapid ipsilateral paw swelling apparent within 24 h that was maintained throughout the 20 days of the study (WT: 139 % control, KO: 132 % control at 24hrs; P < 0.01). The contralateral hind paws showed no swelling at any point in the study. KO mice had significantly less ipsilateral paw swelling than WT animals on day 6-20. This reduction in swelling was found principally in female rather than male mice (female KO: 78 % of WT animals day 20, P < 0.001, n = 5 per genotype). There was no significant difference between the genotypes in either mechanical nociceptive threshold (WT: 2.6 ± 0.3g, KO: 3.4 ± 0.3g) or thermal withdrawal latency (WT: 14.3 ± 0.8 s, KO: 15.4 ± 0.8s) prior to FCA injection. All genotypes developed significant ipsilateral inflammatory mechanical allodynia within 24 h of FCA injection (P < 0.01). Male, but not female mice, also developed significant contralateral mechanical allodynia from day 8 -20 (P < 0.01). All genotypes developed significant ipsilateral, but not contralateral, thermal hyperalgesia within 24 h which was maintained for 20 days (P < 0.01).
These observations suggest that COX-1 contributes to the maintenance of chronic swelling in female mice. COX-1 may also be involved in secondary mechanical allodynia following FCA-induced inflammation.
This work was funded by the Arthritis Research Campaign, UK and the University of Bristol (studentship to NLC).