In this work we studied the local anaesthetic activity of beta-caryophyllene, one of the main components of clove oil obtained from the dried flower-buds of Syzygium aromaticum (Myrtaceae family). We compared its activity to a chemically related compound, caryophyllene oxide. Anaesthetic activity was evaluated in vivo in the rabbit conjunctival reflex test and in vitro in a rat phrenic nerve-hemidiaphragm preparation. Beta-caryophyllene (10(-4) - 1 microg/ml), but not caryophyllene oxide, was able to reduce drastically, in a dose-dependent manner, the electrically evoked contractions of the rat phrenic hemidiaphragm. In the rabbit, conjunctival reflex test treatment with a solution of beta-caryophyllene (10-1000 microg/ml) allowed a dose-dependent increase in the number of stimuli necessary to provoke the reflex. As in the in vitro results, caryophyllene oxide was ineffective also in the in vivo test. In conclusion, these data evidence the local anaesthetic activity of beta-caryophyllene, which appears to be strictly dependent on its chemical structure.
The administration of the ryanodine receptor (RyR) agonist 4-Cmc (0.003-9 nmol per mouse intracerebroventricularly [i.c.v.]) ameliorated memory functions, whereas the RyR antagonist ryanodine (0.0001-1 nmol per mouse i.c.v.) induced amnesia in the mouse passive avoidance test. The role of the type 1, 2, and 3 RyR isoforms in memory processes was then evaluated by inhibiting the expression of the three RyR proteins in the mouse brain. A selective knockdown of the RyR isoforms was obtained by the i.c.v. administration of antisense oligonucleotides (aODNs) complementary to the sequence of RyR1, RyR2 and RyR3 proteins, as demonstrated by immunoblotting experiments. RyR1 (5-9 nmol per mouse i.c.v.) knockdown mice did not show any memory dysfunction. Conversely, RyR2 (1-7 nmol per mouse i.c.v.) and RyR3 (1-7 nmol per mouse i.c.v.) knockdown animals showed an impairment of memory processes. This detrimental effect was temporary and reversible, disappearing 7 d after the end of the aODN treatment. At the highest effective doses, none of the compounds used impaired motor coordination, as revealed by the rota rod test, nor modified spontaneous mobility and inspection activity, as revealed by the hole-board test. In conclusion, the lack of any involvement of cerebral RyR1 was demonstrated. These findings also showed the involvement of type 2 and type 3 RyR in the modulation of memory functions identifying these cerebral RyR isoforms as critical targets underlying memory processes.
1 Effects of substances which are able to alter brain histamine levels on the nociceptive threshold were investigated in mice and rats by means of tests inducing three different kinds of noxious stimuli: mechanical (paw pressure), chemical (abdominal constriction) and thermal (hot plate). 2 A wide range of i.c.v. doses of histamine 2HCI was studied. Relatively high doses were dosedependently antinociceptive in all three tests: 5-100 ,g per rat in the paw pressure test, 5-50 g per mouse in the abdominal constriction test and 50-1I 00 g per mouse in the hot plate test. Conversely, very low doses were hyperalgesic: 0.5 ftg per rat in the paw pressure test and 0.1-1 g per mouse in the hot plate test. In the abdominal constriction test no hyperalgesic effect was observed. 3 The histamine H3 antagonist, thioperamide maleate, elicited a weak but statistically significant dose-dependent antinociceptive effect by both parenteral (10-40mgkg-') and i. 5 Thioperamide-induced antinociception was completely prevented by pretreatment with a nonhyperalgesic i.p. dose of (R)-a-methylhistamine in the mouse hot plate and abdominal constriction tests. Antagonism was also observed when both substances were administered i.c.v. in rats. 6 L-Histidine HCl dose-dependently induced a slowly occurring antinociception in all three tests. The doses of 250 and 500mgkg-', i.p. were effective in the rat paw pressure test, and those of 500 and 1500mgkg'1, i.p. in the mouse hot plate test. In the mouse abdominal constriction test 500 and 1000mgkg'1, i.p. showed their maximum effect 2h after treatment. 8 To ascertain the mechanism of action of the antinociceptive effect of L-histidine and metoprine, the two substances were also studied in combination with the histamine synthesis inhibitor (S)-a-fluoromethylhistidine and with (R)-o-methylhistamine, respectively. L-Histidine antinociception was completely antagonized in all three tests by pretreatment with (S)-a-fluoromethylhistidine HCl (50 mg kg', i.p.) administered 2 h before L-histidine treatment. Similarly, metoprine antinociception was prevented by (R)-a-methylhistamine dihydrogenomaleate 20 mg kg-', i.p. administered 15 min before metoprine. Both (S)-a-fluoromethylhistidine and (R)-a-methylhistamine were used at doses which did not modify the nociceptive threshold when given alone. 9 The catabolism product, 1-methylhistamine, administered i.c.v. had no effect in either rat paw pressure or mouse abdominal constriction tests.10 These results indicate that the antinociceptive action of histamine may take place on the postsynaptic site, and that its hyperalgesic effect occurs with low doses acting on the presynaptic receptor. This hypothesis is supported by the fact that the H3 antagonist, thioperamide is antinociceptive and the H3 agonist, (R)-a-methylhistamine is hyperalgesic, probably modulating endogenous histamine release. L-Histidine and metoprine, which are both able to increase brain histamine levels, are also able to induce antinociception in mice and rats. Involvement of the histaminer...
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