The potential role of spinal cord cyclooxygenase-2 in the development of Freund's complete adjuvant-induced changes in hyperalgesia and allodynia.
Chronic inflammatory conditions produce a state of hyperalgesia which is evident from a few hours to days after administration of an inflammatory stimulus. The molecular mechanisms involved in the initiation of hyperalgesia are not well understood and in this study we have investigated the role of prostaglandins in this process in the rat. Unilateral intraplantar injection of Freund's complete adjuvant produces an immediate localized swelling (oedema) with the development of altered pain responses in the ipsilateral paw such as a reduced threshold to noxious stimuli (hyperalgesia) and lowered thresholds such that normally innocuous stimuli produce a pain response (allodynia). We have monitored levels of cyclooxygenase messenger RNA and prostaglandins in lumbar spinal cord in parallel with these behavioural responses (oedema, hyperalgesia and allodynia) and identified a marked increase in cyclooxygenase-2 messenger RNA (3-fold), maximal at 2-4 h after Freund's complete adjuvant, followed by a significant increase in 6-keto prostaglandin F1alpha and prostaglandin E2 which is maximal by 8 h. Pretreatment of animals with the unselective cyclooxygenase inhibitor indomethacin attenuated oedema (approximately 40%) and allodynia (80-100%), but had no effect on the development of mechanical hyperalgesia. Pretreatment with the cyclooxygenase-2 selective inhibitors DuP 697, flosulide and SC58125 also attenuated allodynia (by 80-100%) but had no effect on the development of oedema or mechanical hyperalgesia. The marked increase in cyclooxygenase-2 messenger RNA in the lumbar spinal cord following intraplantar Freund's complete adjuvant suggests that the cyclooxygenase enzyme and its product may have a role in the adaptive response that occurs in the lumbar spinal cord during a peripheral inflammatory reaction. Pharmacological analysis reveals that prostaglandins are directly involved in the development of allodynia. However, these studies show that the development of mechanical hyperalgesia does not require the production of prostaglandins indicating that more than one pathway mediates the altered pain responses associated with a peripheral inflammatory lesion.
Hay
C H
CH
Department of Biochemistry, Charing Cross and Westminster Medical School, London, U.K.
Trevethick
M A
MA
Wheeldon
A
A
Bowers
J S
JS
de Belleroche
J S
JS
D000818:Animals; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004487:Edema / Q000139:chemically induced / Q000201:enzymology / Q000503:physiopathology; D005528:Foot; D005620:Freund's Adjuvant; D006930:Hyperalgesia / Q000139:chemically induced / Q000201:enzymology* / Q000503:physiopathology; D007213:Indomethacin / Q000494:pharmacology; D007527:Isoenzymes / Q000096:biosynthesis / Q000502:physiology*; D008297:Male; D010146:Pain / Q000139:chemically induced / Q000201:enzymology* / Q000503:physiopathology; D010147:Pain Measurement / Q000187:drug effects; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000502:physiology*; D011453:Prostaglandins / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D013116:Spinal Cord / Q000201:enzymology* / Q000378:metabolism / Q000503:physiopathology*
D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D011453:Prostaglandins; D012333:RNA, Messenger; D005620:Freund's Adjuvant; D011451:Prostaglandin-Endoperoxide Synthases; D007213:Indomethacin