Biomedical subjects

S F Maier

Publications and source records attributed to S F Maier.

At least 109 records · Page 6Linked to original sources

PubMed1994

Subcutaneous formalin produces centrifugal hyperalgesia at a non-injected site via the NMDA-nitric oxide cascade.

Previous work has demonstrated that pain facilitation can occur following injection of subcutaneous irritants, such as formalin. Such studies have focused on apparent pain facilitation induced at the site of irritant injection. Changes in processing of incoming pain information have typically been assumed to result from activation of neurocircuitry intrinsic to the spinal cord. The present series of studies have examined hyperalgesia exhibited at a site distant from the site of irritant injection and have begun to define the neurocircuitry and neuropharmacology underlying this pain enhancement. This work demonstrates that s.c. formalin injected into the dorsum of one hindpaw in rats produces prolonged hyperalgesia as measured by the tailflick test. Hyperalgesia is not mediated solely by circuitry intrinsic to the spinal cord, but rather involves activation of centrifugal pathways originating within the brain and descending to the spinal cord via pathway(s) outside of the dorsolateral funiculus. At the level of the spinal cord, this hyperalgesic state is mediated by an NMDA-nitric oxide cascade, since hyperalgesia can be abolished by administration of either an NMDA antagonist (APV) or a nitric oxide synthesis inhibitor (L-NAME).

2-Amino-5-phosphonovalerate↗

PubMed1994

Neurocircuitry of illness-induced hyperalgesia.

We have previously demonstrated that illness-inducing agents such as lithium chloride (LiCl) and the bacterial cell wall endotoxin lipopolysaccharide (LPS) produce hyperalgesia on diverse pain measures. The present series of studies attempted to identify the neurocircuitry mediating these effects. These studies have demonstrated that illness-inducing agents produce hyperalgesia by activating: (a) peripheral nerves rather than by generating a blood-borne mediator (Expt. 1); (b) vagal afferents, specifically afferents within the hepatic branch of the vagus (Expt. 2); (c) as yet unidentified brain site(s) rostral to the mid-mesencephalon (Expt. 6); (d) a centrifugal pathway that arises from the nucleus raphe magnus, and not from the adjacent nucleus reticularis paragigantocellularis pars alpha (Expts. 4 and 5); (e) a centrifugal pathway in the dorsolateral funiculus of the spinal cord (Expt. 3); and (f) the same centrifugal pathways for diverse illness inducing agents (Expts. 3, 7 and 8). These data call for the re-evaluation of a number of assumptions inherent in previous studies of hyperalgesia.

Animals↗

PubMed1994

The nature of conditioned anti-analgesia: spinal cord opiate and anti-opiate neurochemistry.

The central nervous system contains circuitry that inhibits pain sensitivity (analgesia), as well as circuitry that opposes pain inhibition (anti-analgesia). Activation of analgesia systems and anti-analgesia systems can each be brought under environmental control using classical conditioning procedures. Analgesia can be produced by cues present before and during aversive events such as electric shock, while active inhibition of analgesia comes to be produced by cues never present immediately before or during shock and therefore signal safety. We have recently reported that these analgesia and anti-analgesia systems interact at the level of the spinal cord. A series of 3 experiments were performed to examine how such interactions occur. First, potential opioid mediation of conditioned analgesia was investigated using systemic and intrathecal (i.t.) delivery of opiate antagonists. Conditioned analgesia was found to be mediated by activation of spinal mu and delta opiate receptors. Second, analgesia produced by each of these receptor subtypes was challenged by environmental signals for safety. Analgesias produced by mu and delta opiate agonists were each abolished by safety signals. Third, antagonists/antisera directed against several putative anti-opiate neurotransmitters were tested i.t. to identify which mediate conditioned anti-analgesia at the level of the spinal cord. A cholecystokinin antagonist abolished conditioned anti-analgesia. In contrast, neuropeptide FF antiserum and a kappa opiate antagonist were without effect.

Analgesia↗

PubMed1994

Morphine-induced decreases in in vivo antibody responses.

Endogenous opioids have been shown to be released during acute stress and could play a role in immune modulation and activation of the hypothalamo-pituitary-adrenal axis. We investigated the ability of morphine sulfate to mimic stressor effects on decreases in in vivo antibody responses. Sprague-Dawley and Fischer 344 rats were given an intraperitoneal injection of an antigen, Keyhole limpet hemocyanin (KLH), followed by a single intravenous injection of either saline or varying doses of morphine sulfate. The corticosterone and anti-KLH IgG antibody responses to morphine were measured. A dose-dependent increase in corticosterone was observed. Significantly lower levels of anti-KLH IgG antibodies were observed in morphine-treated animals but these effects were strain and dose dependent. In Sprague-Dawley rats, 3 and 10 mg/kg doses of morphine decreased antibody levels while 1.5, 5, and 15 mg/kg did not change antibody responses. In Fischer 344 rats a dose of 5 mg/kg of morphine decreased antibody levels while 10 and 15 mg/kg did not change antibody responses. These results indicate that morphine can decrease antibody levels and that these decreases are not correlated with elevated levels of corticosterone. To determine if opioid binding is critical to these changes, animals received naltrexone prior to the administration of morphine. Naltrexone partially attenuated corticosterone levels, but completely blocked morphine-induced changes in immune function.

Animals↗

PubMed1994

Route of morphine administration modulates conditioned analgesic tolerance and hyperalgesia.

The present experiments investigated the effects of route of drug injection on two of the phenomena associated with repeated, cued, morphine administration. Experiment 1 examined the degree of situational specificity of analgesic tolerance following 5 days of morphine (5 mg/kg) delivered either subcutaneously (SC) or intravenously (i.v.). Situationally specific tolerance was only observed following i.v. morphine, although nonspecific tolerance was evident in both instances. Experiment 2 indicated that this difference was not due to dose, as neither 2.5 or 7.5 mg/kg SC morphine produced demonstrable situationally specific tolerance. Experiment 3 examined the putative existence of compensatory responses underlying the observed tolerance. Hyperalgesia in response to the environment in which morphine was experienced was evident in animals trained with i.v. morphine, but not in those receiving repeated SC injections. Potential explanations for these effects of route of administration are discussed.

Analgesics↗

PubMed1994

Psychoneuroimmunology. The interface between behavior, brain, and immunity.

Psychoneuroimmunology is the study of interactions between behavior, the brain, and the immune system. This article is designed to provide an overview of this new field for the general psychologist. The existence of bidirectional communication pathways between the brain and the immune system and the implications of this network for behavior are emphasized. Implications are that behavioral-psychological processes ought to be capable of altering immune function and that events that occur as part of immune responses should modulate behavior. Evidence for influences in both of these directions is reviewed. The discussion of psychological modulation of immunity focuses on classical conditioning and stress, whereas that of immune modification of behavior highlights behavioral effects produced by substances released by the immune system. Finally, the adaptive role that such changes might play is considered.

Behavior↗

PubMed1994

Chlordiazepoxide microinjected into the region of the dorsal raphe nucleus eliminates the interference with escape responding produced by inescapable shock whether administered before inescapable shock or escape testing.

Systemic administration of benzodiazepines before exposure to inescapable shock (IS) blocks the enhanced fear conditioning and escape learning deficits that follow exposure to IS, whereas administration before the subsequent behavioral testing eliminates the enhanced fear but not the interference with escape. The failure of benzodiazepines to reduce the IS-produced escape learning deficit when given before testing is inconsistent with a recent proposal that interference with escape is mediated by an IS-induced sensitization of dorsal raphe nucleus (DRN) activity. The present experiments demonstrate that chlordiazepoxide will block both the enhancement of fear and interference with escape responding when given before either IS or testing if microinjected in the region of the DRN. This suggests that systemic benzodiazepines fail to block escape deficits when given before testing because action at a site distant from the DRN counters the effect of the drug at the DRN.

Animals↗

PubMed1993

Interleukin-1 mediates the behavioral hyperalgesia produced by lithium chloride and endotoxin.

The sickness-inducing agents lithium chloride (LiCl) and lipopolysaccharide (LPS) produce a long-lasting facilitation of the nociceptive tailflick reflex. Many of the behavioral and physiological changes produced by illness are mediated by interleukin-1 (IL-1) released from monocytes stimulated by the pathogenic substance. Monocytes also produce an IL-1 receptor antagonist (IL-1ra) which has been sequenced and cloned. The present experiments report that IL-1 can itself produce hyperalgesia as assessed by tailflick to radiant heat, and that recombinant IL-1ra blocks the hyperalgesia produced by LiCl and LPS.

Animals↗

PubMed1993

Modulation of the in vivo antibody response by a benzodiazepine inverse agonist (DMCM) administered centrally or peripherally.

Exposure to stressors can result in changes in immune function. Although there is increasing information concerning the peripheral hormonal and neural mediators of stress-induced changes in immune function, there is little information concerning the central nervous system mechanisms that lead to the peripheral changes. The following experiments examined the possible involvement of the benzodiazepine-GABAA-chloride complex in modulation of the in vivo antibody response. Rats were given either peripheral or intracerebroventricular injections of methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), a drug that has been shown to act at the benzodiazepine-GABAA complex and produces a behavioral state similar to anxiety. Rats were then immunized with keyhole limpet hemocyanin (KLH) and serum levels of KLH-specific antibody were measured for 2 weeks after immunization. Both peripheral and central administration of DMCM modulated the in vivo antibody response. The dose-response relationship of DMCM and changes in antibody levels was nonmonotonic, with high doses resulting in an increase in serum antibody levels and moderate doses resulting in a decrease in serum antibody levels. A possible role of the benzodiazepine-GABAA system in stress-induced immunomodulation is discussed.

Animals↗

PubMed1993

Opioid and nonopioid interactions in two forms of stress-induced analgesia.

Stressful environmental events activate endogenous mechanisms of pain inhibition. Under some circumstances the analgesia is blocked by naloxone/naltrexone ("opioid"), while under others it is not ("nonopioid"). The existence of these two categories of analgesia leads to the question of how they are related. In a collateral inhibition model proposed by Kirshgessner, Bodnar, and Pasternak (1982), opiate and nonopiate mechanisms were viewed as acting in a mutually inhibitory fashion. In the present experiments, rats were exposed to either of two environmental stressors that produce a nonopioid stress-induced analgesia (SIA) following injections of the opiate antagonist naltrexone or agonist morphine. In the presence of naltrexone, SIA produced by either cold water swim (CWS) or social defeat was enhanced. These same SIAs were found to attenuate the analgesic effect of morphine, demonstrating that an activation of opioid systems can inhibit nonopioid analgesias. These results support an inhibitory interaction of opioid and nonopioid mechanisms in some forms of stress-induced analgesia.

Analgesia↗

PubMed1993

Stressor controllability, social interaction, and benzodiazepine systems.

Effects of benzodiazepine receptor-active compounds on inescapable shock-produced changes in social interaction were studied in the rat. Inescapably shocked animals exhibited less social interaction in a novel situation than did escapably shocked or unshocked rats 24 h after shock. Administration of the selective benzodiazepine receptor antagonist flumazenil at the time of shock prevented the decrease in social interaction. Social interaction was unaffected by the same treatment at the time of measurement. Reduction in social interaction induced by inescapable stress endured for 48-72 h following stressor exposure but was absent 168 h after stress. It was subject to antagonist blockade at all measured time points. Stress-induced decreases in social interaction were also blocked by the benzodiazepine chlordiazepoxide given at the time of shock treatment. The receptor antagonist did not reverse this blockade. An inverse agonist, the beta-carboline FG 7142, administered in place of inescapable shock, produced an identical pattern of social interaction in a dose-dependent manner. The inverse agonist effect was also reversed by the antagonist. The results from antagonist, agonist, and inverse agonist treatments all suggest that an endogenous benzodiazepine receptor inverse agonist is released at the time of inescapable shock and is involved in producing the changes in social interaction subsequently measured.

Animals↗

PubMed1993

Factors that modulate inescapable shock-induced reductions in daily activity in the rat.

Most behavioral and neurochemical changes produced by inescapable shock dissipate in 1-3 days. However, daily running activity is depressed for 14-42 days following one to three sessions of inescapable shock. In the present experiments, we sought to determine whether factors known to be important in the development of the short-term effects of exposure to inescapable shock would also be important in the production of the long-term effect of inescapable shock on daily activity. Three factors were examined: a) the escapability of the shock; short-term behavioral changes generally do not occur if the shock is escapable; b) naltrexone pretreatment; the opioid antagonist naltrexone typically prevents many of the short-term behavioral sequelae of inescapable shock; c) treatment with the anxiogenic beta-carboline FG-7142; administration of this compound alone frequently mimics inescapable shock in its ability to transiently disrupt behavior. The inescapable shock-induced reduction in daily activity did not depend upon escapability of the stressor. In addition, naltrexone did not prevent and FG-7142 did not induce the reduction in daily activity associated with stressor exposure.

Animals↗

PubMed1993

Blockade of the hypothalamic-pituitary-adrenal response to stress by intraventricular injection of dexamethasone: a method for studying the stress-induced peripheral effects of glucocorticoids.

Interest in the mechanisms whereby stressors can influence behavior and physiological functioning has involved the use of a variety of methods to prevent the stress-induced release of glucocorticoids, an important and commonly studied stress hormone. We examined the effect of intracerebral ventricular dexamethasone (ICV DEX) on the stress-induced release of adrenocorticotropic hormone (ACTH), corticosterone, plasma epinephrine (E), and plasma norepinephrine (NE). Male Sprague-Dawley rats were stereotaxically implanted with third ventricle ICV cannulae, administered DEX or vehicle, and exposed to 100 1.6-mA tail shocks. Stress hormones were assessed from blood taken during and after the cessation the shock. We report an ICV DEX injection protocol (10 microgram given four times) that results in blocking the stress-induced release of ACTH and corticosterone, and attenuating the stress-induced release of plasma E and NE. We hypothesize that ICV DEX reduces hypothalamic corticotropin releasing hormone (CRH) synthesis and/or release. This method would be especially useful for those studying the effect of pituitary-adrenal hormones on steroid sensitive peripheral targets, such as the immune system.

Adrenocorticotropic Hormone↗

PubMed1993

Dissociation of interference with the speed and accuracy of escape produced by inescapable shock.

Benzodiazepines and naltrexone administered before inescapable shock block behavioral consequences of the inescapable shock such as poor shuttle box escape, reduced activity in reaction to shock, reduced social interaction, and so on. Anxiogenic beta-carboline derivatives such as FG-7142 can produce these effects by themselves. In the present study, neither diazepam nor naltrexone had any effect on the interference with Y-maze choice escape accuracy produced by inescapable shock even though they both eliminated the reduction in Y-maze escape response speed produced by inescapable shock. Analogously, FG-1742 did not lead to a reduction in Y-maze choice escape response accuracy even though it did slow escape responding. These data imply that inescapable shock interferes with escape choice learning and escape response speed by different mechanisms, the former not involving fear-anxiety processes.

Animals↗

PubMed1993

The role of the amygdala and dorsal raphe nucleus in mediating the behavioral consequences of inescapable shock.

It has been argued that exposure to inescapable shock produces later behavioral changes such as poor shuttle box escape learning because it leads to the conditioning of intense fear, which later transfers to the shuttle box test situation and interferes with escape. Both fear, as assessed by freezing, and escape were measured in Sprague-Dawley rats 24 hr after exposure to inescapable shock. Lesions of the basolateral region and central nucleus of the amygdala eliminated the fear that transfers to the shuttle box after inescapable shock, as well as the fear conditioned in the shuttle box by the shuttle box shocks. However, the amygdala lesions did not reduce the escape learning deficit produced by inescapable shock. In contrast, dorsal raphe nucleus lesions did not reduce the fear that transfers to the shuttle box after inescapable shock, but eliminated the enhanced fear conditioning in the shuttle box as well as the escape deficit. The implications of these results for the role of fear and anxiety in mediating inescapable shock effects are discussed.

Amygdala↗

PubMed1993

The amygdala is necessary for the expression of conditioned but not unconditioned analgesia.

Lesions of the basolateral region and central nucleus of the amygdala prevent conditioned analgesia (Helmstetter, 1992). In general, these regions of the amygdala are more critically involved in the expression of conditioned reactions to aversive events than in the mediation of unconditioned reactions. The impact of amygdala lesions on both conditioned and unconditioned analgesia was explored in Sprague-Dawley rats. The lesions completely prevented the expression of conditioned analgesia, but had no effect on unconditioned analgesia.

Amygdala↗

PubMed1993

Anesthesia-induced modulation of in vivo antibody levels: a study of pentobarbital, chloral hydrate, methoxyflurane, halothane, and ketamine/xylazine.

The influence of anesthesia on long-term changes in in vivo antibody levels after antigen challenge was examined. Rats experienced a surgical plane of various anesthetics alone (anesthesia/intact) or in combination with laparatomy (anesthesia/laparatomy) and were given 1 or 3 wk to recover. Antigen, keyhole limpet hemocyanin, was then administered, and antibody levels specific to the antigen were measured during the next 14 days. Comparisons were made between anesthesia-treated animals and home cage controls. Pentobarbital and chloral hydrate produced decreases in in vivo antibody levels even 3 wk after exposure, whereas halothane, methoxyflurane, and ketamine/xylazine did not. Ketamine/xylazine produced moderate but not significant decreases in antibody levels when 1 wk intervened between exposure and antigen administration, but not when 3 wk intervened. Surgery did not produce larger changes in antibody levels than did anesthesia itself. These data suggest the possibility that some anesthetics, per se, may contribute to infection that may occur postoperatively.

Anesthetics↗

PubMed1992

Parallel activation of multiple spinal opiate systems appears to mediate 'non-opiate' stress-induced analgesias.

Pain is powerfully modulated by circuitries within the CNS. Two major types of pain inhibitory systems are commonly believed to exist: opiate (those that are blocked by systemic opiate antagonists and by systemic morphine tolerance) and non-opiate (those that are not). We used intrathecal delivery of mu, delta, and kappa opiate receptor antagonists to examine 3 well-accepted non-opiate stress-induced analgesias. Combined blockade of all 3 classes of opiate receptors antagonized all of the 'non-opiate' analgesias. Further experiments demonstrated that blocking mu and delta or mu and kappa was sufficient to abolish 'non-opiate' analgesias. Combined blockade of kappa and delta receptors was without effect. The clear conclusion is that all endogenous analgesia systems may in fact be opiate at the level of the spinal cord. Phenomena previously thought to be non-opiate appear to involve parallel activation of multiple spinal opiate processes. These findings suggest the need for a fundamental shift in conceptualizations regarding the organization and function of pain modulatory systems in particular, and opiate systems in general.

Analgesia↗