Gen. Pharmac. Vol. 24, No. 5, pp. 1173-1176, 1993 0306-3623/93 $6.00 + 0.00 Printed in Great Britain Pergamon Press Ltd ANTINOCICEPTIVE EFFECTS OF Hi- AND H2-ANTIHISTAMINICS IN MICE NURETTIN ABACIO~LU,* AYSEL BEDIZ, ICLAL (~AKICI, BAHAR TUN(~TANand |LKER KANZIK Gazi University, Faculty of Pharmacy, Department of Pharmacology, Hipodrom, 06330 Ankara, Turkey [Fax 9-90-4-2235018] (Recewed 18February 1993) Abstract--1. Two methods were used to study the analgesic effects of subcutaneous injections of antihistaminics in mice: the p-benzoquinone(PBQ)-writhing test and caudal compression test. 2. Mepyramine, lupitidine (SKF 93479), and famotidine produced significant antinoeiceptive effects dose-dependently, during both the PBQ-writhing and caudal compression tests. 3. However, ranitidine did not reveal any antinociceptive effect. 4. Icotidine (SKF 93319) produced significant antinociception and also augmented the analgesic effect of morphine, on the caudal compression test. 5. However, mepyramine, famotidine, and lupitidine did not affect morphine-induced analgesia on the caudal compression test and displayed a nonsignificant potentiation on morphine-induced analgesia in the PBQ-writhing test. INTRODUCTION In the peripheral nervous system, histamine (HA) produces pain and pruritus (Rosenthal and Minard, 1939; Rosenthal, 1977). Conflicting reports have proposed both inhibition and facilitation of pain perception by Hi-receptors (Rumore and Schlicht- ing, 1985) and there is now anatomical, neurochemi- cal and behavioral evidence supporting the hypothesis that brain H2-receptors are mediators of antinociceptive responses (Glick and Crane, 1978; Netti et al., 1988). The interaction between opioids and histamine has been documented in a number of studies (Ellis et al., 1970; Grosman et al., 1982). Clinical data suggest that some antihistaminics (e.g. hydroxyzine) may produce analgesia in humans, and this effect is synergistic with morphine (Beaver and Feise, 1976; Morichi and Pepeu, 1978). Some recent studies demonstrated that antihistaminics potenti- ated the analgesic action of opioids in mice (Bluhm et al., 1982; Tagashira et al., 1984). In addition, Gogas et al. (1989) suggested that stimulation of opioid receptors lead to antinociception by mechan- isms that included activation of brain H2-receptors. Present experiments were undertaken to assess the analgesic effects of some Hz and H 2 antagonists on two different analgesia tests and the influence of these antagonists on the analgesic action of morphine. *To whom all correspondence should be addressed. MATERIALS AND METHODS Local bred albino mice of either sex weighing between 16-24 g were used. The drugs were injected s.c. and the solutions were adjusted to make an injection volume of 0. I ml per I0 g mouse. The experiments were performed at room temperature (20-24°C). Antinociceptive tests p-Benzoquinone (PBQ)-writhing test. The PBQ-induced writhing assay was performed according to Okun et al. (1963). PBQ (2.5 mg/kg) was injected i.p. This dose caused writhing in all control animals. The test drugs were injected s.c. half an hour before the injection of PBQ. The mice were kept individually for observation and in each case the total number of writhes for the following 30 rain were noted. A "writhe" is described as a stretching of the whole animal so that it looks elongated with the abdomen touching the surface of the table, torsion to one side, drawing up of the hind limbs and usually "sucking in" of the abdomen. The percent pro- tection at each dose level is calculated as follows, for each group of mice: % protection = 100-(experimental/ control) x I00. Caudal compression test. We used an apparatus for produc- ing a uniformly increasing pressure on a mouse tail, consist- ing of two syringes, connected tip-to-tip with each other by means of inelastic, flexible, plastic tubing, filled with fluid according to the method of Green and Young (I 985). A side arm in the tubing is connected to a manometer. The first syringe is positioned vertically, the tip pointing upward. The mouse tail is placed beneath the plunger of this syringe. When pressure is exerted on the plunger of the second syringe by an infusion pump (Harvard), this pressure is communicated through the hydrolic system to the first syringe and thence to the mouse's tail. Uniform depression of the second syringe thus increases the pressure on the tail. The face of the plunger in contact with the tail is a circle, 10 mm in diameter and slightly concave. The manometer reading is taken when the mouse responds by struggling. For comparison the manome- ter readings, in millimeters of mercury from the rest position, were taken for controls and for mice given morphine or other 1173