Influence of restraint stress on endogenous central histamine-induced antinociceptive effect in rats : Studies with histamine N-methyltransferase inhibitor SKF 91488

Histamine as a neurotransmitter participates in modulation of pain transmission within the central nervous system. Exogenous histamine administered intracerebroventricularly (icv) as well as endogenous histamine, after blockage of its catabolism by histamine N-methyltransferase (HNMT) inhibitors, which leads to an increase in endogenous histamine concentrations, produce an antinociceptive effect. On the other hand, there is an activation of the histaminergic system, with the increase in histamine turnover and/or release from neurones, in response to potentially dangerous stimuli disturbing homeostasis, including changes in blood pressure, dehydration and nociceptive stimuli. Therefore, the aim of the present study was to examine the influence of prior restraint immobilisation stress on HNMT inhibitor SKF 91488-induced antinociceptive effect in rats. SKF 91488 (100 μg icv) produced an increase in endogenous histamine concentrations 15 min after treatment in the cerebral cortex (1.09 ± 0.11 vs. 0.61 ± 0.22 nmol/g; p < 0.01), hypothalamus (5.67 ± 0.64 vs. 4.11 ± 0.49 nmol/g; p < 0.01) and medulla oblongata (0.53 ± 0.19 vs. 0.32 ± 0.08 nmol/g; p < 0.05) in comparison to saline-treated group. The effect was accompanied by a dose-dependent (50-100 μg icv) analgesic action both in tail-flick test and paw pressure test (Randall-Selitto test). Prior restraint stress increased SKF 91488-induced effect, however, it did not change central histamine concentrations. The restraint stress alone did not influence central histamine concentrations as well as nociceptive responses. The study confirms that SKF 91488 is an effective in vivo inhibitor of HNMT activity which increases endogenous central histamine concentrations, and thus produces an antinociceptive action. Moreover, prior restraint stress increases endogenous histamine-induced influence on pain transmission, possibly as a result of the activation of the histaminergic system. K e y w o r d s: endogenous histamine, pain perception, restraint stress, rat