Effect of withdrawal of diazepam or morphine treatment on gastric motility (charcoal meal test) in mice: possible role of different central and peripheral receptors.

Increased gastrointestinal motility in mice as one of the withdrawal symptoms of commonly abused drugs like diazepam or morphine and its possible mechanism of action was studied. Male Laka mice (20-25 g) were made addict to either diazepam (20 mg/kg, ip for 7 days) or morphine (10 mg/kg, sc for 9 days). Withdrawal symptoms were noted 24 hr after the last injection of diazepam or morphine. The animals were injected with Ro 15-1788 (flumazenil) (1 mg/kg, ip) or naloxone (2 mg/kg, ip) in the respective group to precipitate the withdrawal symptoms. Gastrointestinal motility was assessed by charcoal-meal test. Animals developed tolerance to acute sedative effect of diazepam, and similarly to the acute nociceptive action of morphine. On abrupt cessation of these drugs after chronic treatment the animals showed hyperlocomotion and hyperreactivity in diazepam withdrawal group and hyperalgesia on hot plate in morphine withdrawal groups, respectively. Increase in gastrointestinal motility was observed in all the drug withdrawal groups. Treatment with respective antagonists, Ro 15-1788 (flumazenil) and naloxone precipitated the withdrawal symptoms. The results suggest the involvement of both central and peripheral receptors of benzodiazepines and opioid (mu) receptors in the withdrawal symptoms of the benzodiazepines and morphine, respectively.

Possible role of histamine receptors in the central regulation of immune responses.

The present study was designed to delineate the role of H1- and H2-histamine receptors in the neuro-immune regulation in rats. The effects of H1- and H2-receptor antagonists on humoral and cell-mediated immune (HI and CMI) responses were investigated after intraperitoneal (i.p.) and intra-cerebroventricular (i.c.v.) administration. HI response was assayed by anti-sheep red blood cell (SRBC) antibody titre in presence and absence of 2-mercaptoethanol (2-ME). The CMI responses were evaluated by delayed type hypersensitivity (DTH) reaction (in vivo), i.e., measurement of footpad thickness, and lymphokine activity such as leucocyte migration inhibition (LMI) test (in vitro). On i.p. administration, both H1- (pheniramine and astemizole) and H2-receptor antagonists (ranitidine and cimetidine) were observed to produce significant enhancement of anti-SRBC antibody response. However, only H2- and not H1-receptor blockers were observed to stimulate CMI response significantly. When administered by icv route, only H2-receptor antagonists caused a statistically significant increase in both HI and CMI responses, while the H1-receptor blockers failed to modify the same. Thus, H2-receptors appear to play a major role in the histaminergic mechanisms involved in immunomodulation both at the level of immunocompetent cells active in the peripheral tissues as well as through the central nervous system structures involved in the central regulation of neuro-immune interaction.

Effect of glutamic acid and ketamine on morphine-induced analgesic response in rats.

Rats were treated with intraperitoneal injections of morphine (10 mg/kg) followed by glutamic acid (20 mg/kg.) and ketamine. (5 mg/kg). Pain thresholds were recorded as tail flick latencies for a period of 23 days and the mean area under curves calculated. Glutamic acid and ketamine, partially blocked the analgesic effects of morphine. Two types of effects were observed. In 4 animals, there was a partial blockade of the response, and in 2 animals there was a complete blockade followed by reversal in both the groups. It is suggested that two different mechanisms one excitatory and one inhibitory may be operating for the interaction of NMDA receptors with the opioid analgesic systems for modulating nociceptive responses.