The effects of compounds active at histamine H3-receptors on morphine-induced antinociception have been investigated in thermal and chemical tests in mice; tail-immersion (50 degrees C) and hot-plate (49 degrees and 55 degrees C) tests and acetic acid-induced writhing. Neither (R)alpha-methylhistamine, a specific agonist, (S)alpha-methylhistamine, a chemical control, nor thioperamide, an antagonist, had any antinociceptive action alone but thioperamide (3 mg kg-1) attenuated the effects of morphine in the tail-immersion test while (R)alpha-methylhistamine (1 mg kg-1), but not the (S) isomer, potentiated its effects in the hot-plate test at 55 degrees C. These results are consistent with the morphine potentiation seen with H1-antagonists and suggest that central histaminergic mechanisms can modulate opioid actions.
Structural and dynamic properties of the extensor digitorum longus (EDL) and soleus muscles of the rat under pentobarbital sodium anesthesia have been determined 4, 28, and 400 days after extirpation of the tibialis anterior and compared with the properties of muscles from the contralateral limb of the same animal. At 4 days the mass of the EDL increased by about 17%, but the maximum tetanic tension and tension per unit cross-sectional area decreased. The soleus showed a slight decrease in mass of about 6%. At 28 days the mass of the EDL had increased to 126% of the control value. Maximum isometric twitch and tetanic tensions increased, whereas tetanic tension per unit cross-sectional area returned to normal values; the number of sarcomeres in series increased, which led to an increase in the whole muscle speed of shortening. It is concluded that the synergistic EDL undergoes compensatory hypertrophy by the addition of contractile material in series and in parallel but without any change in the intrinsic properties of the muscle. The fibers of the antagonistic soleus shorten slightly but are otherwise unchanged.
Central histaminergic modulation of H1 rather than H2-receptors has been shown to modify epileptic activity. Compounds acting on the HIC- and H3-receptors were tested against chemically-induced seizures in mice. Compounds antagonising the microsomal and nuclear intracellular receptors (HIC) only modified seizures at doses where toxicity was observed. Antagonists of the histamine H3-receptor (thioperamide and burimamide) only potentiated the severity of clonic convulsions induced by picrotoxin, while impromidine (i.c.v.), an antagonist with H2-agonist activity, inhibited leptazol-induced seizures. The H3-agonist, (R)alpha-methylhistamine, potentiated chemically-induced seizures, but at lower doses there was slight inhibition.
Epilepsy-prone strains of animal are often used as models for epilepsy. Susceptibility of the DBA/2 mouse to audiogenic seizures is age-related, beginning as soon as they can hear (~day 14) and is virtually lost by day 40 [1]. Controversy exists over the relationship between whole brain levels of 5-HT and noradrenaline and the audiogenic seizure susceptibility in the DBA/2 mouse [2]. Alterations in CNS histamine levels and function have been associated with epileptic seizures in rodents [3] and to date investigations into CNS histamine levels in this mouse strain have not been published. Thus we have measured levels of histamine and its major metabolite in 4 distinct brain regions in male DBA/2 mice compared with a nonaudiogenic-sensitive mouse strain (BKTO). Materials and methodsBoth audiogenic-sensitive (DBA/2) and non-audiogenic-sensitive (BKTO, Bantin & Kingman, Hull) mice were bred and housed at University of East London. Groups of 10 male mice of both strains, at 14, 21, 28, 35 and 42 days of age were killed by cervical dislocation. Brains were rapidly removed onto ice and dissected into 4 regions: cerebral cortex, hypothalamus, cerebellum and rest (mid-brain + brain stem). Perchloric acid (0.4 M) and EDTA (5 mM) were added to each sample. Samples were sonicated on ice and stored at -70°C. Histamine and t-methylhistamine were determined using an HPLC-fluorimetric method and GCMS [4]. Matched groups of mice were tested for audiogenic seizure susceptibility [5]. Data was analysed by ANOVA and appropriate post-tests. All animal work conformed to national animal legislation. Results and discussionBKTO mice did not exhibit audiogenic susceptibility. Maximal audiogenic susceptibility in the DBA/2 mouse occurred at day 21 and was almost lost 3 weeks later (Fig. 1 A). Our findings on the age-related audiogenic susceptibility of the DBA/2 mice agree with previous reports [1, 5].As assessment for audiogenic seizures might alter CNS histamine and t-methylhistamine levels, these were measured in mice which had not been subjected to any loud noises. Levels of histamine were highest in the hypothalamus (~10 nmol/g) and were similar in both strains with the highest levels being found on day 21 and then declining with age Inflamm. res. 52, Supplement 1 (2003) Fig. 1. Groups of 10 male DBA/2 & BKTO mice at weekly intervals were used to determine (A) mean audiogenic seizure scores by the method in [5] (1 = wild running, 2 = clonus, 3 = tonus, 4 = respiratory arrest. Inter-strain differences (Kruskal Wallis ANOVA) and (B) mean cerebellar histamine levels (pmol/g) + SD using HPLC-fluorimetry [4].
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