To characterize the mechanism of the analgesic action of H1 antihistaminics the effects of a new, highly selective agonist, 2-(3-trifluoromethylphenyl)histamine dihydrogenmaleate (FMPH), and of the better known H1 agonist, 2-thiazolylethylamine (2-TEA), were studied on pain threshold by means of three different kinds of tests for nociception (mouse hot plate and abdominal constriction, and rat paw pressure tests). Low doses of both substances (2.65 and 6.5 microg/animal i.c.v. for FMPH in the hot plate and paw pressure tests, and 0.3 microg/rat i.c.v. for 2-TEA in the paw pressure test) were slightly but significantly hypernociceptive. The selective H1 receptor antagonist, pyrilamine maleate (10-30 mg/kg s.c.), induced a dose-dependent antinociception in all three tests, and both FMPH and 2-TEA prevented its effect, but not that of morphine, thus indicating action on H1 receptors. The same low doses of FMPH were also able to enhance animals' spontaneous motility and curiosity. High doses of FMPH (13.23-132.3 microg/mouse i.c.v.) raised the pain threshold, but due to the severe motor impairment evidenced by the rota rod test, this cannot be considered as real antinociception. An increase in the pain threshold lacking any motor impairment was observed for tenfold higher doses of 2-TEA (3 and 10 microg/mouse i.c.v.). This may be due to action on H2 receptors, with the reported relative potency of 2-TEA for H1 and H2 receptors being about 12:1. It is therefore suggested that H1 receptor activation increases sensitivity to noxious stimuli.