Endogenous opioids: role in prostaglandin-dependent and -independent fever.
This study evaluated the participation of mu-opioid-receptor activation in body temperature (T(b)) during normal and febrile conditions (including activation of heat conservation mechanisms) and in different pathways of LPS-induced fever. The intracerebroventricular treatment of male Wistar rats with the selective opioid mu-receptor-antagonist cyclic d-Phe-Cys-Try-d-Trp-Arg-Thr-Pen-Thr-NH(2) (CTAP; 0.1-1.0 microg) reduced fever induced by LPS (5.0 microg/kg) but did not change T(b) at ambient temperatures of either 20 degrees C or 28 degrees C. The subcutaneous, intracerebroventricular, and intrahypothalamic injection of morphine (1.0-10.0 mg/kg, 3.0-30.0 microg, and 1-100 ng, respectively) produced a dose-dependent increase in T(b). Intracerebroventricular morphine also produced a peripheral vasoconstriction. Both effects were abolished by CTAP. CTAP (1.0 microg icv) reduced the fever induced by intracerebroventricular administration of TNF-alpha (250 ng), IL-6 (300 ng), CRF (2.5 microg), endothelin-1 (1.0 pmol), and macrophage inflammatory protein (500 pg) and the first phase of the fever induced by PGF(2alpha) (500.0 ng) but not the fever induced by IL-1beta (3.12 ng) or PGE(2) (125.0 ng) or the second phase of the fever induced by PGF(2alpha). Morphine-induced fever was not modified by the cyclooxygenase (COX) inhibitor indomethacin (2.0 mg/kg). In addition, morphine injection did not induce the expression of COX-2 in the hypothalamus, and CTAP did not modify PGE(2) levels in cerebrospinal fluid or COX-2 expression in the hypothalamus after LPS injection. In conclusion, our results suggest that LPS and endogenous pyrogens (except IL-1beta and prostaglandins) recruit the opioid system to cause a mu-receptor-mediated fever.
Fraga
Daniel
D
Departamento de Farmacologia, Setor de Ciências Biológicas, Universidade Federal do Paraná, CEP 81540-970, Curitiba, Paraná, Brazil.
Machado
Renes R
RR
Fernandes
Luíz C
LC
Souza
Glória E P
GE
Zampronio
Aleksander R
AR
D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D005334:Fever / Q000139:chemically induced / Q000378:metabolism*; D007213:Indomethacin / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D009020:Morphine / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D018847:Opioid Peptides / Q000378:metabolism*; D011453:Prostaglandins / Q000378:metabolism*; D011749:Pyrogens / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000701:Analgesics, Opioid; D016861:Cyclooxygenase Inhibitors; D008070:Lipopolysaccharides; D009842:Oligopeptides; D018847:Opioid Peptides; D011453:Prostaglandins; D011749:Pyrogens; D017450:Receptors, Opioid, mu; C089773:phenylalanyl--cysteinyl-tyrosyl-tryptophyl-arginyl-penicillaminyl-threoninamide; D009020:Morphine; D007213:Indomethacin