Vol. 294, Issue 3, 1131-1136, September 2000

The Importance of the Hypothalamo-Hypophyseal-Adrenal Axis to the Anti-Inflammatory Actions of the -Opioid Agonist PNU-50,488H in Rats with Adjuvant Arthritis¹

Jodie L. Wilson, John J. Carmody and Judith S. Walker

School of Physiology and Pharmacology, University of New South Wales, Sydney, New South Wales, Australia

Possible contributions of the hypothalamo-hypophyseal-adrenal axis to the development of adjuvant-induced arthritis and therapeutic actions of the prototypical -opioid agonist PNU-50,488H (PNU-50) were studied in DA rats. Paw edema, nociception, histological and radiological joint damage, and tumor necrosis factor- release by peritoneal macrophages were measured in adrenalectomized (ADX) and sham-operated (SHO) arthritic animals (drug-treated and untreated groups). Disease developed earlier in ADX rats (paw edema was first apparent 11 days postadjuvant compared with day 13 in SHO animals) and remained more severe in that group. Twice-daily PNU-50 treatment completely prevented the development of edema in the SHO group but was effective in the ADX animals only on day 18. PNU-50 substantially reduced the pooled severity index (combined quantitative edema, histological and radiological assessments) at day 18 in both SHO and ADX rats and to an equal extent. During disease development, the paws of SHO, but not ADX, rats became hyperalgesic; paradoxically, ADX animals were hyperalgesic during PNU-50 treatment, but the drug produced analgesia in SHO animals. Compared with cells harvested from healthy animals, macrophages from arthritic rats released about twice as much tumor necrosis factor- after lipopolysaccharide stimulation. It was concluded that the hypothalamo-hypophyseal-adrenal axis influences the development of adjuvant arthritis and plays a partial role in the therapeutic action of the -agonist PNU-50.