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Biomedical subjects

L A Dykstra

Publications and source records attributed to L A Dykstra.

At least 37 records · Page 2Linked to original sources
PubMed1996

The role of serotonergic receptors in the effects of mu opioids in squirrel monkeys responding under a titration procedure.

This experiment was conducted to determine whether drugs acting on brain serotonin modulate the effects of the mu opioid, morphine, as measured by the squirrel monkey shock titration procedure and, if so, whether serotonergic modulation is mediated via specific 5HT receptor subtypes. Under this procedure, electric shock was delivered to the monkey's tail and scheduled to increase once every 15 s from 0.01 to 2.0 mA in 30 steps. Five responses on a lever during the 15-s shock period terminated the shock for 15 s, after which the shock resumed at the next lower intensity. The intensity below which monkeys maintained shock 50% of the time (median shock level or MSL) and rate of responding (RR) in the presence of shock were determined under control conditions and after administration of morphine alone and in combination with various serotonergic compounds. Morphine increased median shock level and decreased rate of responding in a dose-dependent manner. These effects of morphine was attenuated by the 5HT1A receptor agonists, 8-OH-DPAT [(+)-8-hydroxy-2(di-n-propylamino tetralin HBr] and ipsapirone. The effects of morphine were not altered by the 5HT1A receptor antagonist, NAN-190 [1-(2-methoxyphenyl-4-[4-(2-phthalimido) butyl] piperazine HBr], and 5HT2 receptor antagonist, ketanserin, the 5HT3 receptor antagonist, MDL 72222 [3-tropanyl-3,5-dichlorobenzoate], the alpha 2 adrenergic antagonist, yohimbine, or the alpha2 adrenergic agonist, clonidine. These results suggest that 5HT1A receptors may be involved in the effects of morphine in the shock titration procedure, whereas 5HT2, 5HT3 and alpha 2 adrenergic receptors do not appear to play a role in morphine's effects in this procedure.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1996

Discriminative-stimulus effects of morphine in combination with alpha- and beta-noradrenergic agonists and antagonists in rats.

Studies have shown that the noradrenergic system is involved in the analgesic effects of opioids and in the expression and development of physical signs of opioid withdrawal. The purpose of the present experiment was to determine if the noradrenergic system was involved in the discriminative effects of morphine in rats trained to discriminate 5.6 mg/kg morphine from saline under a fixed-ratio schedule of food presentation. A range of doses of morphine (0.3-10.0 mg/kg) produced dose-dependent increases in morphine-appropriate responding without substantial decreases in response rate. Several experiments were conducted to determine whether a number of noradrenergic agonists and antagonists 1) substitute for morphine or 2) alter the discriminative-stimulus effects of morphine when administered concurrently. The alpha 2 agonist clonidine (0.003-0.1 mg/kg), the alpha 1 antagonist prazosin (0.1-10.0 mg/kg), the alpha 2 antagonist yohimbine (0.1-10.0 mg/kg), the beta 2 agonist salbutamol (0.03-10.0 mg/kg), and the beta antagonist propranolol (1.0-10.0 mg/kg), neither substituted for morphine nor altered the discriminative-stimulus effects of morphine when administered in combination. These data suggest that the noradrenergic system is not involved in the discriminative-stimulus effects of 5.6 mg/kg morphine in rats.

Adrenergic Agents↗
PubMed1996

Evidence for sympathetic and adrenal involvement in the immunomodulatory effects of acute morphine treatment in rats.

The present study examined the involvement of the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis in the immunomodulatory effects of acute morphine treatment in rats. Chlorisondamine, a ganglionic blocker, was used to assess the involvement of sympathetic and sympathoadrenal activity. Adrenalectomized rats were used to assess the involvement of the adrenal cortex, which is regulated primarily by hypothalamic-pituitary-adrenal axis activity, and the adrenal medulla, which is regulated primarily by sympathetic activity. The results showed that both chlorisondamine and adrenalectomy antagonize morphine's suppressive effects on the proliferative response of splenic lymphocytes to concanavalin A (Con A), lipopolysaccharide or ionomycin/phorbol myristate acetate. Chlorisondamine, but not adrenalectomy, antagonizes morphine's suppressive effects on phytohemagglutinin (PHA)-stimulated proliferation of splenic lymphocytes and interferon-gamma production by stimulated splenocytes. Adrenalectomy, but not chlorisondamine, blocks morphine's suppressive effects on the proliferative response of blood lymphocytes to Con A or PHA. Neither chlorisondamine nor adrenalectomy alters morphine's suppressive effect on splenic natural killer cell cytotoxicity. Collectively, these results suggest that sympathoadrenal activity is involved in the suppressive effects of acute morphine treatment on the proliferative response of splenic T and B cells to Con A, lipopolysaccharide or ionomycin/phorbol myristate acetate. Morphine's suppressive effects on the proliferative response of splenic T cells to PHA and the production of interferon-gamma by stimulated splenocytes also involve sympathetic activity, but not sympathoadrenal activity. The results suggest further that morphine's suppressive effects on the proliferative response of blood T cells to Con A or PHA do not involve sympathetic activity, but rather adrenocortical activity. Neither sympathetic nor adrenocortical activity appears to be involved in morphine's suppressive effect on splenic natural killer cell cytotoxicity.

Adrenalectomy↗
PubMed1996

Assessment of the involvement of central nervous system and peripheral opioid receptors in the immunomodulatory effects of acute morphine treatment in rats.

The present study assessed the involvement of opioid receptors both in the central nervous system (CNS) and in the periphery (i.e., on immunocytes) in the immune alterations produced by acute morphine treatment in rats. The first experiment showed that the in vitro suppressive effects of morphine on the mitogen-stimulated proliferation of splenic and blood lymphocytes are produced only by a very high concentration of morphine and are not naltrexone-reversible. These results suggest that the in vitro immunomodulatory effects of morphine are not mediated by classical opioid receptors on immunocytes. A second experiment showed that s.c. doses of N-methylnaltrexone that do not gain access to the CNS, as determined by the tail-withdrawal assay, do not antagonize the suppressive effects of a single, s.c. injection of morphine on the mitogen-stimulated proliferation of splenic and blood lymphocytes, splenic natural killer cell activity and the production of interferon-gamma by stimulated splenocytes. Only a high s.c. dose of N-methylnaltrexone that does gain access to the CNS, as determined by the tail-withdrawal assay, blocks morphine's immunomodulatory effects. A third experiment demonstrated that N-methylnaltrexone is 4 to 5 log units more potent in antagonizing most of the immune alterations produced by a single, s.c. injection of morphine when administered i.c.v. than s.c. Taken together, the results of the present study strongly suggest that CNS opioid receptors play an important role in the immune alterations produced by acute morphine treatment in rats.

Analgesics, Opioid↗
PubMed1996

Evidence for the involvement of the caudal region of the periaqueductal gray in a subset of morphine-induced alterations of immune status.

This study was directed at determining whether morphine's immunomodulatory effects are mediated through the periaqueductal gray (PAG). The initial study showed that microinjection of morphine (0.0, 0.4, 4.0, or 40.0 micrograms/rat) into the lateral ventricle induces pronounced dose-dependent reductions in lymphocyte proliferation to T- and B-cell mitogens, natural killer cell cytotoxicity, and the production of interleukin-2 and interferon-gamma. In contrast, microinjection of morphine (0.0, 0.004, 0.04, 0.4, or 4.0 micrograms/rat) into the caudal aspect of the PAG induced dose-dependent alterations in natural killer cell cytotoxicity, but had no effect on lymphocyte proliferation or cytokine production. These results indicate that opioid receptors in the PAG are involved in the regulation of natural killer cell activity, but are not associated with morphine's effects on proliferation or cytokine production. A subsequent study showed that the effect of morphine in the PAG is restricted to the more caudal aspects of the PAG because microinjections of morphine into the rostral aspects do not result in any alteration of immune status. To determine that the activation of opioid receptors in the PAG is not only sufficient, but is required for morphine's effects on natural killer cell activity, N-methylnaltrexone was administered into the PAG (0, 0.0001, 0.001, or 0.01 micrograms/rat) before the systemic administration of morphine (15 mg/kg), a dose that induces pronounced alterations of natural killer cell activity. The results showed that the administration of N-methylnaltrexone directly into the PAG antagonized morphine's effects on natural killer cell activity, which indicate that activation of opioid receptors within the PAG are required for morphine to alter natural killer cell activity. Collectively, this study showed that activation of opioid receptors within the more caudal aspects of the PAG are required for morphine to induce alterations in splenic natural killer cell activity. The results also suggest that other brain regions are responsible for morphine's effect on lymphocyte proliferation and cytokine production.

Adjuvants, Immunologic↗
PubMed1995

The role of serotonin in the effects of opioids in squirrel monkeys responding under a titration procedure: I. Kappa opioids.

The goal of the present study was to determine whether the serotonin (5-HT) system is involved in the effects of kappa opioids as measured with the squirrel monkey shock titration procedure. With this procedure, electric shock was delivered to the monkey's tail and scheduled to increase once every 15 sec from 0.01 to 2.0 mA in 30 steps. Monkeys responded under a fixed ratio 5 schedule to determine the level at which shock intensity was maintained. The intensity below which monkeys maintained shock 50% of the time, or the median shock level (MSL), and the rate of responding in the presence of shock (RR) were determined after the administration of saline and all drug combinations. The kappa opioids U50,488 and spiradoline increased MSL and decreased RR in a dose-dependent manner. The effects of U50,488 and spiradoline on both RR and MSL were enhanced in all three monkeys by the 5-HT2 antagonists ketanserin and pirenperone and in one monkey by another 5-HT2 antagonist, LY 53857. The effects of U50,488, but not spiradoline, were enhanced to a lesser degree by the 5-HT1A receptor agonist 8-OH-DPAT. The effects of U50,488 but not altered by the receptor agonist DOI, the 5-HT3 receptor antagonist MDL 72222 or the alpha-1 adrenergic receptor antagonist prazosin. These results suggest that the effects of kappa opioids in the shock titration procedure probably involve serotonergic mechanisms that are modulated via 5-HT2 and, perhaps, 5-HT1A receptors. Moreover, these interactions probably reflect nonspecific decreases in RR rather than alterations in the antinociceptive effects of kappa opioids.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1995

Mechanisms whereby macrophage-derived nitric oxide is involved in morphine-induced suppression of splenic lymphocyte proliferation.

Previous research by our laboratory demonstrated that in vivo administration of morphine to rats suppresses concanavalin-A (Con-A)-stimulated proliferation of splenic lymphocytes in a dose-dependent, naltrexone-reversible manner. More recently, we showed that morphine-induced suppression of Con A-stimulated proliferation of lymphocytes depends on an increase in macrophage production of nitric oxide (NO) in splenocyte cultures. The present study investigated effector mechanisms through which morphine-induced increases in macrophage-derived NO decrease lymphocyte proliferation in Con A-stimulated splenocyte cultures. The results show that the addition of hemoglobin, a scavenger of extracellular NO, to Con A-stimulated splenocyte cultures dose-dependently attenuates the suppressive effect of morphine on proliferation. The addition of superoxide dismutase, a scavenger of superoxide anions, to splenocyte cultures does not antagonize the suppressive effect of morphine on Con A-stimulated proliferation. The addition of either methylene blue or 6-anilino-5, 8-quinolinedione (LY 83583), two inhibitors of soluble guanylate cyclase, to splenocyte cultures dose-dependently antagonizes the suppressive effect of morphine on Con A-stimulated proliferation. Taken together with our previous results, the present results suggest that in vivo administration of morphine increases the synthesis and extracellular release of NO from macrophages in Con A-stimulated splenocyte cultures. The results further suggest that the formation of the oxidant peroxynitrite through a reaction between NO and superoxide anion does not contribute significantly to the suppression of lymphocyte proliferation; instead, the activation of soluble guanylate cyclase by NO in target cells, most likely the lymphocytes, accounts more completely for the morphine-induced suppression of lymphocyte proliferation.

Aminoquinolines↗
PubMed1994

Macrophage-derived nitric oxide is involved in the depressed concanavalin A responsiveness of splenic lymphocytes from rats administered morphine in vivo.

The present study examined the role of macrophage-derived nitric oxide in the suppressive effect of in vivo morphine administration on Con A-stimulated proliferation of splenic lymphocytes in rats. The results showed that concentrations of nitrite are significantly greater in Con A-stimulated splenocyte cultures from morphine-treated rats than in cultures from saline-treated rats, and that the depletion of macrophages from splenocyte cultures abolishes the suppressive effect of morphine on Con A-stimulated proliferation. Moreover, the addition of NG-monomethyl-L-arginine (NMMA) to Con A-stimulated splenocyte cultures attenuates the suppressive effect of morphine on mitogenic responsiveness. The addition of excess L-arginine to splenocyte cultures containing NMMA reverses the effect of NMMA and restores morphine's suppressive effect on Con A-stimulated proliferation, but the addition of D-arginine to splenocyte cultures containing NMMA does not restore the suppressive effect of morphine. Taken together, these findings demonstrate that the suppressive effect of in vivo morphine administration on Con A-stimulated proliferation of splenic lymphocytes involves macrophage-derived nitric oxide.

Animals↗
PubMed1994

Pavlovian conditioning of morphine-induced alterations of immune status: evidence for peripheral beta-adrenergic receptor involvement.

The present studies examined the involvement of peripheral beta-adrenergic receptor activity in the establishment and expression of conditioned morphine-induced alterations of immune status. Previous work in our laboratory has shown that morphine's immunomodulatory effects can become conditioned to environmental stimuli which predict drug administration. These immune alterations include conditioned changes in natural killer cell activity, interleukin-2 production, and mitogen-induced lymphocyte proliferation. During the training phase of these experiments, Lewis rats received two conditioning sessions during which a subcutaneous injection of 15 mg/kg morphine sulfate was paired with exposure to a distinctive environment. On the test day, rats were reexposed to the conditioned stimulus prior to sacrifice. Saline or nadolol (0.002, 0.02, 0.2, or 2.0 mg/kg) was administered either prior to the training sessions or prior to the test session. Administration of nadolol prior to training did not affect the development of conditioned alterations of immune status. Conversely, nadolol administration prior to testing completely attenuated the expression of a subset of the conditioned morphine-induced changes in immune status. Taken together, these studies suggest that whereas peripheral beta-adrenergic receptor activity is not required for the establishment of conditioned morphine-induced alterations of immune status, it is involved in the expression of a subset of these conditioned immunomodulatory effects.

Animals↗
PubMed1994

Pharmacological analysis of the rate-decreasing effects of mu and kappa opioids in pigeons.

The present study investigated the rate-decreasing effects of several mu (morphine and l-methadone) and kappa (bremazocine, U69,593 and U50,488) opioid agonists in pigeons. Mu and kappa agonists were examined alone, in combination with naltrexone or the mu-selective opioid antagonist, beta-funaltrexamine (beta-FNA), and in pigeons treated chronically with U50,488. Naltrexone was equipotent in shifting the morphine, l-methadone and bremazocine dose-effect curves to the right, but was less potent in shifting the U69,593 dose-effect curve and did not shift the U50,488 dose-effect curve. Beta-FNA shifted the l-methadone dose-effect curve to the right but did not shift the bremazocine, U69,593 or U50,488 dose-effect curves. Pigeons that developed tolerance to U50,488 following daily administration were cross-tolerant to bremazocine but not to l-methadone. Taken together, these experiments indicate that the rate-decreasing effects of morphine and l-methadone are mediated by mu opioid receptors, whereas the rate-decreasing effects of bremazocine, U69,593 and U50,488 in pigeons differ depending on the pharmacological procedures used to assess their effects.

Animals↗
PubMed1994

Pavlovian conditioning of morphine-induced alterations of immune status: evidence for opioid receptor involvement.

Prior work in our laboratory has shown that morphine's immunomodulatory effects can become conditioned to environmental stimuli that predict drug administration. These immune alterations include conditioned changes in natural killer cell activity, interleukin-2 production, and mitogen-induced lymphocyte proliferation. The present study examined the involvement of opioid receptor activity in the establishment and expression of conditioned morphine-induced alterations of immune status. During the training phase of the experiment, Lewis rats received two conditioning sessions during which a subcutaneous injection of 15 mg/kg morphine sulfate was paired with exposure to a distinctive environment. On the test day, animals were re-exposed to the distinctive environment alone prior to sacrifice. Saline or naltrexone (0.3, 1.0, 3.0 or 10.0 mg/kg) was administered during either the training or the test session. Administration of naltrexone prior to training antagonized the development of all of the conditioned alterations of immune status including changes in the mitogenic responsiveness of splenocytes, suppression of natural killer cell activity, and interleukin-2 production by splenocytes. Naltrexone administration prior to testing also was effective in antagonizing the expression of a subset of morphine-induced conditioned alterations in immune status. Taken together, these studies indicate that opioid receptor activity is involved in the establishment of conditioned morphine-induced immune alterations, as well as in the expression of a subset of these conditioned alterations of immune status.

Animals↗
PubMed1994

Discriminative stimulus effects of phencyclidine: pharmacologically specific interactions with delta 9- and delta 8-tetrahydrocannabinol.

Rats were trained to discriminate a dose of 1.75 mg/kg phencyclidine (PCP) from saline. During substitution tests, both PCP (0.3-10.0 mg/kg) and the non-competitive NMDA antagonist, MK-801 (0.01-0.3 mg/kg) substituted for the PCP stimulus in a dose-dependent manner. In contrast, delta 9-tetrahydrocannabinol (delta 9-THC, 0.1-5.6 mg/kg) and delta 8-tetrahydrocannabinol (delta 8-THC, 0.3-5.6 mg/kg) failed to substitute for the PCP stimulus, up to doses that substantially decreased rate of responding. However, both delta 9-THC and delta 8-THC partially attenuated the discriminative stimulus effects of the PCP training dose. Furthermore, a dose of 3.0 mg/kg delta 9-THC shifted the PCP dose-effect curve for discriminative stimulus effects to the right and shifted the PCP dose-effect curve for rate of responding to the left. The attenuation of the PCP stimulus by delta 9-THC lacked a strong dose-dependent relationship and was observed both at doses which did not alter rate of responding, as well as at doses which substantially decreased rate. In contrast to the effects observed with delta 9-THC and delta 8-THC, morphine, d-amphetamine and chlordiazepoxide failed to attenuate the discriminative stimulus effects of PCP, even at doses that markedly decreased rate of responding. The present findings suggest that delta 9-THC and delta 8-THC alter the discriminative stimulus effects of PCP in a pharmacologically specific manner.

Animals↗
PubMed1994

Antinociceptive and response rate-altering effects of kappa opioid agonists, spiradoline, enadoline and U69,593, alone and in combination with opioid antagonists in squirrel monkeys.

Effects of the kappa opioid agonists, spiradoline (U62,066), enadoline (CI-977) and U69,593, were examined alone and in combination with the opioid antagonists quadazocine and beta-funaltrexamine in squirrel monkeys that responded under a schedule of shock titration. When given alone, each of these agonists increased the intensity at which the monkeys maintained shock 50% of the time (median shock level, MSL). Lower doses of spiradoline, enadoline and U69,593 increased response rates in some monkeys and higher doses decreased response rates in all monkeys. When given in combination with the opioid antagonist quadazocine, the dose-effect curves of each agonist, both for MSL and response rates, were shifted to the right in a dose-related and parallel manner. The slopes for the regression lines of the Schild plots for each agonist-quadazocine interaction approximated unity and apparent pA2 values for quadazocine in combination with these agonists ranged between 6.68 and 6.81 for MSL and between 6.63 and 6.87 for response rate. The effects of these agonists were not changed by an 8.0 mg/kg dose of beta-funaltrexamine that markedly antagonized the effects of morphine. These results parallel those previously obtained with other kappa agonists, such as bremazocine and U50,488 and suggest that the antinociceptive effects of spiradoline, enadoline and U69,593 in the shock-titration procedure in squirrel monkeys relate to activity at non-mu, probably kappa, opioid receptors.

Analgesics↗
PubMed1993

Morphine antagonizes U50,488's effects in a squirrel monkey shock titration procedure.

To determine whether a mu opioid agonist modulates the effects of a kappa opioid agonist in squirrel monkeys responding under a shock titration procedure, morphine was administered in combination with an ED75 dose of U50,488. Morphine (0.03-0.3 mg/kg) did not alter U50,488's early peak effects (15-25 min post-injection), but dose dependently antagonized U50,488's later effects (40-100 min post-injection); these doses of morphine shifted the U50,488 dose-effect curve < 1/4 log unit to the right. After 6-8 weeks of daily morphine administration, higher doses of morphine (0.3-3.0 mg/kg) shifted the U50,488 dose-effect curve > 1/2 log unit to the right. Morphine still did not antagonize early peak effects of the ED75 dose of U50,488, but antagonized early and late effects of a lower dose. Thus, morphine is a weak kappa antagonist in the shock titration procedure. In addition to its low affinity for kappa receptors, morphine's kappa antagonist activity is limited by its mu agonist effects, particularly in the non-morphine-tolerant monkey.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1993

Alterations of immune status induced by the sympathetic nervous system: immunomodulatory effects of DMPP alone and in combination with morphine.

The aim of the present study was to explore the involvement of the sympathetic nervous system (SNS) in the immunomodulatory effects of morphine in Lewis rats and to assess the effects of alterations in SNS activity on immune status. In the first experiment, sympathetic tone was elevated by administering the ganglionic stimulant 1,1-dimethyl-4-phenylpiperazinium (DMPP) in doses of 0, 0.01, 0.1, and 1.0 mg/kg, sc, 5 min before the sc administration of 15 mg/kg morphine or saline. Animals were sacrificed 1 h after the morphine injection and multiple in vitro immune assays were then conducted. Although DMPP did not significantly enhance morphine's suppressive effects in the spleen and blood mitogen stimulation assays or the splenic natural killer (NK) cell assay, DMPP alone produced effects on immune status in saline-treated animals. Therefore, a second experiment was conducted to examine the immunomodulatory effects of increasing peripheral sympathetic outflow in greater detail. Animals were administered a wider dose range of DMPP (0, 0.005, 0.05, 0.5, and 5.0 mg/kg, sc) 30 min prior to sacrifice and an expanded repertoire of immune assays was conducted. DMPP dose-dependently suppressed the mitogenic responsiveness of splenic T lymphocytes, splenic NK cell activity, and interleukin-2 (IL-2) and gamma-interferon production by stimulated splenocytes. DMPP did not alter the total number of splenic leukocytes or the proliferative response of splenic B lymphocytes. In the mesenteric lymph nodes, DMPP had no effect on mitogenic responsiveness, the production of IL-2 or the total number of leukocytes. In the blood, however, DMPP increased mitogenic responsiveness at intermediate doses and decreased proliferation at higher doses. DMPP also dose-dependently decreased the number of blood leukocytes/ml. Taken together, these results indicate that increasing peripheral sympathetic outflow results in profound effects on immune status that depend upon the degree to which SNS activity is altered, the compartment of the immune system, and the lymphocyte subtype.

Adjuvants, Immunologic↗