THE POTENTIAL ROLE OF SPINAL-CORD CYCLOOXYGENASE-2 IN THE DEVELOPMENTOF FREUNDS 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 inflamm atory stimulus. The molecular mechanisms involved in the initiation of hyperalgesia are not well understood and in this study we have invest igated the role of prostaglandins in this process in the rat. Unilater al intraplantar injection of Freund's complete adjuvant produces ail i mmediate localized swelling (oedema) with the development of altered p ain responses in the ipsilateral paw such as a reduced threshold to no xious stimuli (hyperalgesia) and lowered thresholds such that normally innocuous stimuli produce a pain response (allodynia). We have monito red levels of cyclooxygenase messenger RNA and prostaglandins in lumba r spinal cord in parallel with these behavioural responses (oedema, hy peralgesia and allodynia) and identified a marked increase in cyclooxy genase-2 messenger RNA (3-fold), maximal at 2-4 h after Freund's compl ete adjuvant, followed by a significant increase in 6-keto prostagland in F-1 alpha and prostaglandin E-2 which is maximal by 8 h. Pretreatme nt of animals with the unselective cyclooxygenase inhibitor indomethac in attenuated oedema (approximately 40%) and allodynia (80-100%), but had no effect on the development of mechanical hyperalgesia. Pretreatm ent with the cyclooxygenase-2 selective inhibitors DuP 697, flosulide and SC58125 also attenuated allodynia (by 80-100%) but had no effect o n the development of oedema or mechanical hyperalgesia. The marked inc rease in cyclooxpgenase-2 messenger RNA in the lumbar spinal cord foll owing intraplantar Freund's complete adjuvant suggests that the cycloo xygenase enzyme and its product may have a role in the adaptive respon se that occurs in the lumbar spinal cord during a peripheral inflammat ory reaction. Pharmacological analysis reveals that prostaglandins are directly involved in the development of allodynia. However; these stu dies show that the development of mechanical hyperalgesia does not req uire the production of prostaglandins indicating that more than one pa thway mediates the altered pain responses associated with a peripheral inflammatory lesion. (C) 1997 IBRO.