Tumor necrosis factor, interleukin-1 and interleukin-8 mediate the nociceptive activity of the supernatant of LPS-stimulated macrophages.

It has been suggested that the supernatant of LPSstimulated macrophages (macrophage nociceptive factor, MNF) promotes nociception in mice. Intraperitoneal administration of MNF induced dose-related writhing, which reached a plateau between 18 and 26 min after injection and decreased within 60 min. The release of MNF was inhibited by the pretreatment of the macrophages with cycloheximide, a protein synthesis inhibitor, or with the glucocorticoid dexamethasone. Cyclooxygenase inhibitors, such as indomethacin or paracetamol, had no effect. The MNF-induced nociception was inhibited in a dose-related manner by pretreatment of the animals with indomethacin, paracetamol or dexamethasone. Pretreatment of the animals with the sympatholytics guanethidine and atenolol partially reduced the MNF nociception, which was abolished by the combination of guanethidine or atenolol with indomethacin. The preincubation of MNF with antisera against TNF-alpha, IL-1 or IL-8 partially inhibited its nociceptive effect. Intraperitoneal injection of a mixture of the recombinants cytokines TNF-alpha, IL-1 and IL-8 mimicked MNF nociception. The individual injection of these cytokines was unable to induce the nociceptive effect. In conclusion, our data suggest that the nociceptive activity of the supernatant of LPSstimulated macrophages is explained by the presence of TNF-alpha, IL-1 and IL-8, the nociceptive activity of which (in mice) seems to be due to the release of cyclooxygenase and sympathetic metabolites.

A new mechanism of action of dipyrone: blockade of the release of a nociceptive factor from macrophages

Rat macrophage monolayers pre-treated with endotoxin release into the incubating fluid a factor (MW >10,000) capable of inducing writhing in mice (MNF). This release was inhibited by dipyrone (3.5-35 microng/ml) but not by indomethacin (0.5-2 microng/ml). Writhing in mice induced by the factor is blocked by dipyrone (0.5-50 mg/kg) and indomethacin (0.5-2 mg/kg). These results indicate that in addition to the previously described direct blockade of hyperalgesia by dipyrone, this drug may also affect the release of MNF, wich induces in vivo nociception through the release of prostaglandin-like substances

A new mechanism of action of dipyrone: blockade of the release of a nociceptive factor from macrophages.

Rat macrophage monolayers pre-treated with endotoxin release into the incubating fluid a factor (MW greater than 10,000) capable of inducing writhing in mice (MNF). This release was inhibited by dipyrone (3.5-35 micrograms/ml) but not by indomethacin (0.5-2 micrograms/ml). Writhing in mice induced by the factor is blocked by dipyrone (0.5-50 mg/kg) and indomethacin (0.5-2 mg/kg). These results indicate that in addition to the previously described direct blockade of hyperalgesia by dipyrone, this drug may also affect the release of MNF, which induces in vivo nociception through the release of prostaglandin-like substances.