The importance of brain PGE2 inhibition versus paw PGE2 inhibition as a mechanism for the separation of analgesic and antipyretic effects of lornoxicam in rats with paw inflammation.
OBJECTIVE
Lornoxicam is a non-selective cyclooxygenase inhibitor that exhibits strong analgesic and anti-inflammatory effects but a weak antipyretic effect in rat models. Our aim was to investigate the mechanism of separation of potencies or analgesic and antipyretic effects of lornoxicam in relation to its effect on prostaglandin E2 (PGE2) production in the inflammatory paw and the brain.


METHODS
A model of acute or chronic paw inflammation was induced by Freund's complete adjuvant injection into the rat paw. Lornoxicam (0.01-1 mg/kg), celecoxib (0.3-30 mg/kg) or loxoprofen (0.3-30 mg/kg) was administered orally to the rats and the analgesic and antipyretic effects were compared. The paw hyperalgesia was assessed using the Randall-Selitto test or the flexion test. Dorsal subcutaneous body temperature was measured as indicator of pyresis. After the measurement of activities, the rats were sacrificed and the PGE2 content in the paw exudate, cerebrospinal fluid or brain hypothalamus was measured by enzyme-immunoassay.


RESULTS
In a chronic model of arthritis, lornoxicam, celecoxib and loxoprofen reduced hyperalgesia with an effective dose that provides 50% inhibition (ED50) of 0.083, 3.9 and 4.3 mg/kg respectively, whereas the effective dose of these drugs in pyresis was 0.58, 0.31 and 0.71 mg/kg respectively. These drugs significantly reduced the PGE2 level in paw exudate and the cerebrospinal fluid. In acute oedematous rats, lornoxicam 0.16 mg/kg, celecoxib 4 mg/kg and loxoprofen 2.4 mg/kg significantly reduced hyperalgesia to a similar extent. On the other hand, lornoxicam did not affect the elevated body temperature, whereas celecoxib and loxoprofen significantly reduced the pyrexia to almost the normal level. These drugs significantly reduced the PGE2 level in inflamed paw exudate lo almost the normal level. On the other hand, lornoxicam did not change PGE2 level in the brain hypothalamus, whereas celecoxib and loxoprofen strongly decreased it.


CONCLUSIONS
Lornoxicam exhibits strong analgesic but weak antipyretic effects in rats with paw inflammation. Such a separation of effects is related to its efficacy in the reduction of PGE2 levels in the paw and brain hypothalamus.
Futaki
Nobuko
N
Pharmacology Laboratory, Medicinal Research Laboratories, Taisho Pharmaceutical Co. Ltd, Kita-ku, Saitama-shi, Saitama, Japan. nobuko.futaki@po.rd.taisho.co.jp
Harada
Masahiro
M
Sugimoto
Masanori
M
Hashimoto
Yuki
Y
Honma
Yusuke
Y
Arai
Iwao
I
Nakaike
Shiro
S
Hoshi
Keiko
K
D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000188:drug therapy; D000068579:Celecoxib; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D015232:Dinoprostone / Q000134:cerebrospinal fluid / Q000378:metabolism; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D005121:Extremities; D005334:Fever / Q000188:drug therapy*; D005620:Freund's Adjuvant; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy; D008297:Male; D010147:Pain Measurement; D010666:Phenylpropionates / Q000494:pharmacology / Q000627:therapeutic use; D010894:Piroxicam / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D011917:Rats, Inbred Lew; D017208:Rats, Wistar; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D010666:Phenylpropionates; D011720:Pyrazoles; D013449:Sulfonamides; D010894:Piroxicam; C040656:loxoprofen; D005620:Freund's Adjuvant; C059451:lornoxicam; D000068579:Celecoxib; D015232:Dinoprostone