PubMed · 9283400
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F Black, J Hughes. 1997-07-02. Venepuncture.. https://doi.org/10.7748/ns1997.07.11.41.49.c7452
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Activation of neurons in the ventromedial medulla by electrical stimulation or by microinjection of opioid or cholinergic agonists produces antinociception that is mediated in part by spinally-projecting noradrenergic neurons. Several lines of evidence indicate that these noradrenergic neurons are located in the pontine A7 catecholamine cell group. For example, anatomical studies have demonstrated that neurons in the ventromedial medulla project to the noradrenergic neurons in the A7 catecholamine cell group that provide the major noradrenergic innervation of the spinal cord dorsal horn. In addition, electrical and chemical stimulation of A7 neurons produces antinociception that can be reduced by intrathecal injection of alpha2-adrenoceptor antagonists. The present studies provide more direct evidence that activation of neurons in the ventromedial medulla produces antinociception by activating noradrenergic neurons in the A7 cell group. Neurons in the ventromedial medulla were stimulated by microinjecting the cholinergic agonist carbachol (5 microg) into sites in the nucleus raphe magnus or the nucleus gigantocellularis pars alpha of pentobarbital anesthetized Sprague-Dawley rats. In some experiments, the local anesthetic tetracaine (10 microg) was then microinjected near the A7 cell group to inactivate the spinally-projecting noradrenergic neurons. In other experiments, cobalt chloride (100 mM) was microinjected near the A7 cell group to block synaptic activation of spinally-projecting noradrenergic neurons. Microinjection of carbachol into sites in the ventromedial medulla produced antinociception, assessed using the tail flick test, that lasted more than 60 min. However, the effects of carbachol were attenuated by microinjection of either tetracaine or cobalt into sites near the A7 cell group neurons identified by tyrosine hydroxylase-immunoreactivity. Similar injections of tetracaine or cobalt more than 500 microm from the A7 neurons did not alter the antinociceptive effect of carbachol. These results support the conclusion that the antinociception produced by activating neurons in the ventromedial medulla is mediated in part by the subsequent activation of spinally-projecting noradrenergic neurons in the A7 cell group.
Spherical nanoparticulate drug carriers made of poly(d,l-lactic acid) with controlled size were designed. A local anesthetic, lidocaine, a small hydrophobic molecule, was incorporated in the core with loadings varying from about 7 to 32% (w/w) and increasing with the particle size. Particles with sizes from about 250 to 820 nm and low polydispersity were prepared with good reproducibility; the polymer concentration (at constant surfactant concentration) governed the particle size. The large particles with a high loading ( approximately 30%) showed under in vitro conditions a slow release over 24-30 h, the medium sized carriers (loading of approximately 13%) released the drug over about 15 h, whereas the small particles with small loading ( approximately 7%) exhibited a rapid release over a couple of hours. It seems that the drug release rate is related to the state (crystallized or dispersed) of the drug incorporated in the polymer matrix.
The endothelium-dependent and -independent relaxant effect of procaine was examined in isolated rat aortic rings. Procaine induced relaxation of arteries precontracted with phenylephrine or with 60 mM K+ in a concentration-dependent manner (0.01-3 mM). Procaine (1 mM) inhibited the transient contraction induced by caffeine (10 mM) in Ca2+-free Krebs solution. Removal of the endothelium caused a rightward shift of the concentration-response curve for procaine. N(G)-Nitro-L-arginine (L-NNA, 10-100 microM), N(G)-nitro-L-arginine methyl ester (L-NAME, 100 microM) and methylene blue (1-10 microM) significantly attenuated the procaine-induced relaxation without affecting the maximal response. L-Arginine (1 mM) partially but significantly antagonized the effect of L-NAME (100 microM). Pretreatment of endothelium-intact aortic rings with procaine (1 mM) or with acetylcholine (10 microM) significantly elevated the tissue contents of cyclic GMP and this increase was inhibited in the presence of 100 microM L-NNA. Tetrapentylammonium ions (1-3 microM) reduced the procaine-induced relaxation in both endothelium-intact and -denuded arteries. Tetrapentylammonium ions (3 microM) did not affect the procaine-induced relaxation of 60 mM K+-contracted arteries. Tetraethylammonium ions (3 mM) inhibited the procaine-induced relaxation. In contrast, iberiotoxin (100 nM), glibenclamide (3 microM), 4-aminopyridine (3 mM) and indomethacin (10 microM) had no effect. These results indicate that the procaine-induced relaxation may be mediated through multiple mechanisms. A substantial portion of the procaine-induced relaxation in rat aorta was caused by nitric oxide but not by other endothelium-derived factors. The activation of tetrapentylammonium- and tetraethylammonium-sensitive K+ channels contributes in part to the procaine-induced vasorelaxation. Besides, procaine may directly inhibit both external Ca2+ entry and internal Ca2+ release in aortic smooth muscle cells.