The immunopotentiator effects of nefopam.

The effects of opiate analgesics and non-steroidal anti-inflammatory drugs on the immune functions have been reported. The effect of the non-opiate analgesic nefopam on the immune functions has not yet been investigated. Male Swiss albino mice were treated with either heat killed E. coli or saline. They were classified into 12 groups. The effects of subacute (15 mg/kg/12 h S.C. daily for one week) and chronic (10 mg/kg/12 h S.C. daily for one month) treatment with nefopam on the levels of interferon-gamma (IFN-gamma) and total immunoglobulins were examined in both normal and immunized mice. Also, the effect of the chronic administration of nefopam on the phagocytic activity of peritoneal macrophage was evaluated in both normal and immunized mice. Subacute and chronic administration of nefopam induced no significant raise in the level of interferon-gamma (IFN-gamma) or in the level of total immunoglobulins in non-immunized animals, while subacute and chronic treatment with nefopam augmented markedly the immunization induced increase of level of interferon-gamma (IFN-gamma). Furthermore, chronic treatment with nefopam potentiated significantly the production of total immunoglobulin induced by heat killed E. coli. Chronic treatment with nefopam also was associated with significant enhancement of innate immune response reflected in the pronounced increase in the phagocytic activity of macrophages in non-immunized and immunized animals. The enhancement of phagocytic activity of macrophages by nefopam in immunized animals was significantly higher than that of non-immunized animals. These findings revealed that nefopam has the ability to trigger the immune response for bacterial antigen. The mechanism behind the immunostimulatory effect of nefopam requires further investigation, but it may be due, at least in part, to the inhibitory effect of nefopam on the serotonin and norepinephrine reuptake at nerve endings. In conclusion, our findings postulated that nefopam stimulated the immune functions and improved the defence mechanism. This information may be of future therapeutic value in diseases that need immunologic enhancement.

Attenuation of morphine tolerance and dependence by aminoguanidine in mice.

The effect of aminoguanidine, an inducible nitric oxide synthase (iNOS) inhibitor, on morphine-induced tolerance and dependence in mice was investigated in this study. Acute administration of aminoguanidine (20 mg/kg, p.o.) did not affect the antinociceptive effect of morphine (10 mg/kg, s.c.) as measured by the hot plate test. Repeated administration of aminoguanidine along with morphine attenuated the development of tolerance to the antinociceptive effect of morphine. Also, the development of morphine dependence as assessed by naloxone-precipitated withdrawal manifestations was reduced by co-administration of aminoguanidine. The effect of aminoguanidine on naloxone-precipitated withdrawal was enhanced by concurrent administration of the non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, dizocilpine (0.25 mg/kg, i.p.) or the non-specific nitric oxide synthase (NOS) inhibitor, l-N(G)-nitroarginine methyl ester (l-NAME; 5 mg/kg, i.p.) and antagonized by concurrent administration of the nitric oxide (NO) precursor, l-arginine (50 mg/kg, p.o.). Concomitantly, the progressive increase in NO production, but not in brain glutamate level, induced by morphine was inhibited by repeated administration of aminoguanidine along with morphine. Similarly, co-administration of aminoguanidine inhibited naloxone-induced NO overproduction, but it did not inhibit naloxone-induced elevation of brain glutamate level in morphine-dependent mice. The effect of aminoguanidine on naloxone-induced NO overproduction was potentiated by concurrent administration of dizocilpine or l-NAME and antagonized by concurrent administration of l-arginine. These results provide evidence that blockade of NO overproduction, the consequence of NMDA receptor activation, by aminoguanidine, via inhibition of iNOS, can attenuate the development of morphine tolerance and dependence.