Biomedical subjects

L R Flores

Publications and source records attributed to L R Flores.

5 recordsLinked to original sources

PubMed1996

Potential role of the autonomic nervous system in the immunosuppressive effects of acute morphine administration.

These studies investigated the role of the autonomic nervous system in mediating the immunosuppressive effect of morphine on blood lymphocyte proliferation in rats. To determine the contribution of the autonomic nervous system, rats were pretreated with the ganglionic blocker chlorisondamine (5 mg/kg) prior to morphine (7 mg/kg) administration. Ganglionic blockade with chlorisondamine completely antagonized the inhibitory actions of morphine, suggesting that intact ganglionic transmission was required for the inhibition to occur. Blockade of postganglionic parasympathetic neurotransmission with atropine methylbromide (1 mg/kg) or blockade of sympathetic neurotransmission with the alpha-adrenoceptor antagonist phentolamine (1 mg/kg) did not attenuate the suppressive effect of morphine. Blockade of beta-adrenoceptors with propranolol (2.5 mg/kg) resulted in partial antagonism, but this action was not shared by the peripherally acting beta-adrenoceptor antagonist nadolol (6 mg/kg). These results suggest that the inhibitory effect of morphine on blood lymphocyte proliferation may be mediated through activation of the autonomic nervous system; however, individual blockade of either the parasympathetic or sympathetic division of the autonomic nervous system was not sufficient to antagonize this immunosuppressive effect.

Animals↗

PubMed1995

Mechanisms of morphine-induced immunosuppression: effect of acute morphine administration on lymphocyte trafficking.

These studies investigated the potential mechanisms by which acute morphine administration inhibits peripheral blood lymphocyte activity in the rat. As reported previously, blood lymphocyte proliferative responses to concanavalin A were found to be suppressed by 70% 2 hr after administration of morphine (10 mg/kg). In the present study, a more selective mu receptor agonist, fentanyl (0.05 mg/kg), was found to similarly inhibit blood lymphocyte proliferation. Pretreatment with the opioid receptor antagonist naltrexone (5 mg/kg) completely blocked the inhibitory actions of morphine (7 mg/kg). Several different approaches were undertaken to determine whether the depressed blood lymphocyte proliferative response after opioid receptor stimulation was due to an effect on circulating lymphocyte number. First, it was found that morphine administration was accompanied by a 30% decrease in the absolute number of circulating lymphocytes. Fluorescence-activated cell sorter analysis revealed that the decrease was not selective for any specific subpopulation of T lymphocyte. Furthermore, the relative distribution of circulating monocytes, neutrophils or eosinophils was not altered by morphine treatment. The morphine-induced lymphopenia was abolished in adrenalectomized rats, suggesting that this redistribution effect was mediated by the release of adrenal hormones. However, on correcting for the decrease in lymphocyte number by using Ficoll-separated lymphocyte cultures, the proliferative responses of blood lymphocytes remained significantly depressed compared with control values. Collectively, these data suggest that both an adrenal-dependent lymphopenia and an opioid-induced decrease in responsiveness to mitogenic stimulation contribute to the overall antiproliferative effect of morphine on blood lymphocytes.

Adrenalectomy↗

PubMed1994

Acute immunosuppressive effects of morphine: lack of involvement of pituitary and adrenal factors.

We have previously reported that morphine inhibits Concanavalin A-stimulated blood lymphocyte proliferation in a dose-dependent manner. Maximal (80%) inhibition by morphine occurred with a dose of 10 mg/kg 2 hours after drug administration. Concurrent with this suppressive effect was a 2- to 4-fold increase in plasma corticosterone concentrations. In the present study, we examined the potential contribution of the hypothalamic-pituitary-adrenal axis to the suppressive effects of acute morphine exposure. To assess the role of glucocorticoids, rats were pretreated with the steroid receptor antagonist RU486 (20 mg/kg) 30 min before morphine (10 mg/kg) administration. A significant inhibition of lymphocyte activity occurred with morphine in the absence or presence of RU486 pretreatment. Consistent with a mechanism independent of glucocorticoids, adrenalectomy also failed to attenuate the inhibitory actions of morphine. To examine the potential role of pituitary hormones in the suppressive effect, similar experiments were carried out in hypophysectomized animals. In sham-operated or hypophysectomized animals, morphine was found to be equally effective in suppressing lymphocyte proliferation. These results suggest that factors elaborated from intact pituitary or adrenal glands are not required for the acute inhibitory effects of morphine on peripheral blood lymphocyte activity.

Adrenal Cortex Hormones↗

PubMed1993

Immunosuppression by morphine is mediated by central pathways.

We reported previously that a single systemic injection of morphine (10 mg/kg) to rats profoundly suppressed mitogen-induced proliferation of blood lymphocytes by a receptor-mediated mechanism. The present study examined whether this immunosuppressive effect of morphine is mediated by opioid receptors located at either peripheral or central sites. First, the effects of systemic morphine administration on analgesia, mitogen-stimulated lymphocyte proliferation and corticosterone secretion were compared to those observed after the systemic administration of N-methylmorphine, a quaternary derivative which does not readily penetrate the blood-brain barrier. In contrast to systemically administered morphine, the i.p. injection of N-methyl-morphine (20 mg/kg) was without any effect on lymphocyte proliferation, plasma corticosterone concentrations or analgesic responses. Secondly, the effects of morphine and N-methylmorphine after central administration were compared. Within 2 hr after the microinjection of either morphine (10 micrograms/2 microliters) or N-methylmorphine (15 micrograms/2 microliters) into the third ventricle, blood lymphocyte responses were inhibited by 70%, plasma corticosterone concentrations were significantly elevated and maximal analgesic responses were present. Finally, microinjection of morphine (1 microgram/0.2 microliter) into the anterior hypothalamus inhibited blood lymphocyte proliferation by 50% without producing analgesia or a significant increase in plasma corticosterone. These findings suggest that central opioid pathways are involved in the immunosuppressive effects of morphine and these pathways may be distinct from those participating in opioid-induced analgesia and adrenal activation.

Animals↗

PubMed1993

Development of antisera selective for m4 and m5 muscarinic cholinergic receptors: distribution of m4 and m5 receptors in rat brain.

A portion of the cDNA sequence corresponding to the third intracellular loop of either the m4 or m5 muscarinic cholinergic receptor was ligated into the pRIT23 or pET-3a expression vector, respectively. The expressed fusion proteins were purified and used to develop selective polyclonal antisera to the m4 and m5 muscarinic receptors. These antisera were used in an immunoprecipitation protocol to examine quantitatively the distribution of receptor subtypes in regions of rat brain. The density of m4 receptors in rat brain increased in the caudal to rostral direction. The highest levels of m4 receptors were detected in the striatum (1280 fmol/mg) and olfactory tubercle (750 fmol/mg). Low levels of m5 receptors were detected in several brain regions (< 25 fmol/mg). By combining the previously determined receptor densities for the m1, m2, and m3 receptors and results obtained with the newly developed antisera to m4 and m5 receptors, it was determined that 86-99% of the [3H]quinuclidinyl benzilate binding sites in several brain regions were immunoprecipitated. In addition to measuring receptor densities in rat brain, the immunoprecipitation protocol was used to quantify muscarinic receptor levels in tissues reported to express mRNA encoding the m4 receptor. Thus, although only m4 mRNA has been detected in rabbit lung, NG108-15 cells, and N1E-115 cells, both rabbit lung and NG108-15 cells possess both m2 (rabbit lung, 27%; NG108-15 cells, 31%) and m4 (rabbit lung, 55%; NG108-15, 42%) receptors, whereas N1E-115 cells were found to have both m1 (15%) and m4 (65%) receptors. These antisera will be useful in studies of receptor regulation and in determining alterations in density that may occur after pharmacological or physiological manipulations and in various disease states.

Animals↗