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Biomedical subjects

D J Mayer

Publications and source records attributed to D J Mayer.

At least 73 records · Page 4Linked to original sources
PubMed1984

Nonspecific convulsions are induced by morphine but not D-Ala2-methionine-enkephalinamide at cortical sites.

Cortical application of morphine (25, 100 and 400 micrograms) induced cortical spikes in a dose-related fashion and, at 400 micrograms, behavioral and electrographic seizures. These electrographic seizures were not opiate specific since this activity occurred undiminished in naltrexone-pretreated animals and was even potentiated in animals pretreated for 6 days with increasingly higher doses of systemic morphine. In contrast to the effects induced by morphine, the most consistent electrographic effect of cortically applied D-Ala2-methionine-enkephalin (DALA) and methadone was a depression of cortical EEG. These results support the hypothesis that the cortex and spinal cord together form the anatomical substrate of the documented nonspecific convulsive action of high systemically administered doses of morphine.

Animals↗
PubMed1984

Potentiation of opiate analgesia and apparent reversal of morphine tolerance by proglumide.

Exogenous cholecystokinin selectively antagonizes opiate analgesia, which suggests that endogenous cholecystokinin may act physiologically as an opiate antagonist and may play a role in opiate tolerance. The use of the selective cholecystokinin antagonist proglumide provided a test of these hypotheses in rats that were either inexperienced with or tolerant to opiates. Proglumide potentiated analgesia produced by morphine and endogenous opiates and seemed to reverse tolerance. These results suggest that endogenous cholecystokinin systems oppose the action of opiates.

Analgesia↗
PubMed1984

Fear is not critical to classically conditioned analgesia: the effects of periaqueductal gray lesions and administration of chlordiazepoxide.

A high correlation between fear and analgesia classically conditioned to footshock in rats has been reported in the literature. However, it has never been directly tested whether or not fear is in fact causal to the production of conditioned analgesia. We therefore tested whether conditioned analgesia could be elicited in the absence of fear by employing two independent methods of fear suppression. First, areas of the periaqueductal gray (PAG) previously implicated in fear were selectively lesioned. Lesions of the dorsolateral PAG significantly attenuated conditioned analgesia and markedly decreased fear responses. Second, fear was attenuated via administration of chlordiazepoxide (CDP). Rats which had been conditioned while in the presence of CDP showed no reduction in conditioned pain inhibition. These results demonstrate that: (1) fear is not causal to classically conditioned analgesia and (2) the anatomical substrates for fear and conditioned analgesia are distinct but partially overlapping. The fact that fear is not a critical antecedent for classically conditioned analgesia suggests that classical conditioning techniques may be applied clinically to increase the effectiveness of some analgesic manipulations.

Animals↗
PubMed1984

Dorsolateral funiculus and intraspinal pathways mediate vaginal stimulation-induced suppression of nociceptive responding in rats.

In rats, stimulation of the vaginal cervix with a glass rod reliably produces analgesia, as measured by the tail-flick test. The present studies sought to identify the neural substrates underlying this potent pain inhibition by examining the effects of decerebration, spinalization and bilateral dorsolateral funiculus (DLF) lesions on vaginal stimulation-produced analgesia (VSPA). These studies indicate that the neural circuitry mediating VSPA is contained within the caudal brainstem and spinal cord, since decerebration did not reduce VSPA when compared with sham-operated controls. A significant though markedly reduced level of analgesia was induced in spinalized rats, indicating that VSPA involves both intraspinal and descending pathways. This descending pathway, originating within supraspinal nuclei of the caudal brainstem, projects to the spinal cord via the DLF, since DLF lesions and spinalization produced equivalent reductions in VSPA compared to sham-operated controls. These results, considered in the light of previous electrophysiological and anatomical findings, indicate that the ventral medullary region may be the source of the descending DLF projection mediating VSPA.

Animals↗
PubMed1984

Opiate and non-opiate analgesia induced by inescapable tail-shock: effects of dorsolateral funiculus lesions and decerebration.

Previous studies have demonstrated that inescapable tail-shock can produce either non-opiate or opiate short-term analgesia, dependent on the number of shocks delivered. Additionally, extended exposure to inescapable tail shock can produce long-term, opiate analgesic effects. Several lines of investigation suggest that the psychological dimension of perceived controllability may powerfully influence these phenomena in that each form of opiate analgesia can only be produced following exposure to inescapable, rather than equal amounts and distribution of escapable, shock. This has suggested that these opiate analgesias result from the organism's learning that it has no control over shock. Although it has been assumed that the opiate and non-opiate analgesias induced by tail shock may be subserved by neural circuitry similar to that mediating morphine analgesia and other forms of environmentally induced analgesia, no direct evidence exists to support this assumption. The present study sought to provide an initial attempt at defining the neural circuitry involved in these phenomena by examining the effect of bilateral dorsolateral funiculus (DLF) lesions and decerebration. These experiments revealed that pathways within the spinal cord DLF are critical for the production of short-term non-opiate analgesia, short-term opiate analgesia, and long-term opiate analgesia since bilateral DLF lesions abolished all three pain inhibitory effects. Additionally, it was found that decerebration did not attenuate either the short-term non-opiate or short-term opiate analgesia induced by inescapable tail shock. Combining the observations that these non-opiate and opiate short-term effects are not reduced by decerebration yet are abolished by DLF lesions clearly delimits the source of descending pain inhibition as being within the caudal brainstem.

Animals↗
PubMed1984

The neurochemical basis of footshock analgesia: the role of spinal cord serotonin and norepinephrine.

Previous studies have demonstrated that brief front paw and brief hind paw shock produce potent opiate and non-opiate analgesia, respectively. Additionally, opiate analgesia can be classically conditioned by using either front paw shock or hind paw shock as the unconditioned stimulus. Front paw footshock-induced analgesia (FSIA), hind paw FSIA, and classically conditioned analgesia are similar in that each is mediated by a medullospinal pathway. However, the neurochemistry of these medullospinal connections has never been investigated. One question which arises is whether any of these phenomena are mediated by monoaminergic neurotransmitters at the level of the spinal cord. The present series of experiments examined the effect of depleting spinal serotonin (5-HT) and combined depletion of spinal 5-HT and norepinephrine (NE) on front paw FSIA, hind paw FSIA, and classically conditioned analgesia. Hind paw FSIA and classically conditioned analgesia were not attenuated by either of these neurochemical manipulations. Front paw FSIA was significantly reduced by both 5-HT depletion and combined 5-HT and NE depletion. To assess the relative importance of spinal 5 HT and NE in front paw FSIA, NE and 5-HT antagonists were injected onto the lumbosacral cord prior to shock exposure. Attenuation of front paw FSIA by equimolar doses of the monoamine blockers was much greater following injection of the 5-HT blocker than after the NE blocker. These data indicate that spinal 5-HT and, apparently to a lesser extent, spinal NE mediate front paw (opiate) FSIA whereas neither 5-HT nor NE appears to mediate hind paw FSIA or classically conditioned analgesia.

Afferent Pathways↗
PubMed1984

Comparison of the effects of ventral medullary lesions on systemic and microinjection morphine analgesia.

The effects of electrolytic lesions of the nucleus raphe magnus (NRM), nucleus reticularis paragigantocellularis (PGC) and nucleus raphe alatus (NRA) on analgesia elicited in the rat from systemic morphine and morphine microinjection into the periaqueductal gray (PAG) were evaluated using the tail flick test. No consistent change in baseline pain sensitivity was observed following lesions of the NRM, PGC or NRA. To determine the effect of ventral medullary lesions on systemic morphine analgesia, pain sensitivity was assessed prior to and 40 min after 6 mg/kg morphine administration (i.p.) at 2 days preceding lesioning and 5, 12 and 19 days post-lesion. NRM and PGC lesions produced only slight reductions in analgesia at 5 days after surgery. It was observed that large NRM, large PGC, and NRA lesions significantly attenuated analgesia evaluated at 12 days post-lesion. Smaller lesions confined within the NRM or PGC were reliably less effective than the larger lesions in reducing analgesia. In a subsequent study, 5 micrograms morphine in 0.5 microliter saline was microinjected into the ventral PAG at the level of the dorsal raphe. Identical testing procedures were used and the analgesia was assessed at 2 days before lesioning and 5 and 12 days post-lesion. In contrast to the previous study, large NRM lesions abolished analgesia as early as 5 days following lesioning. Small NRM lesions were less effective and PGC lesions were generally ineffective in attenuating analgesia induced by morphine microinjection. We conclude that the NRA may act as a functional unit in the mediation of systemic morphine analgesia. In contrast, analgesia elicited from intracerebral (PAG) morphine microinjection is mediated via the NRM.

Analgesia↗
PubMed1984

Analgesia produced by electrical stimulation of the brain.

Electrical stimulation of the brain can produce a selective and potent modulation of responding to noxious stimuli in animals and man. The influence of various stimulation parameters is discussed. Brain stimulation at numerous loci results in analgesia. The most well characterized regions are the mesencephalic periaqueductal gray matter and the medullary raphe nuclei. One pain inhibitory system activated by brain stimulation involves a neural circuit from the PAG to the medullary raphe nuclei. Output from there descends via the DLF to modulate pain transmission in the dorsal horn of the spinal cord. Other analgesia systems are also activated by brain stimulation. Compelling evidence implicates endogenous opiates in SPA. Monoaminergic neurotransmitters are also involved in SPA. Brain stimulation has proven to be useful for the management of some forms of intractable pain in man.

Analgesia↗
PubMed1984

Non-serotonergic origins of the dorsolateral funiculus in the rat ventral medulla.

Cells within the ventral medulla whose axons descend to the spinal dorsal horn via the dorsolateral funiculus (DLF) play an important role in pain modulation. Previous evidence suggests that this pathway is primarily serotonergic. We have examined this hypothesis directly using combined retrograde horseradish peroxidase/serotonin immunohistochemical staining. Cells of the ventral medulla contributing to the DLF were found to be largely non-serotonergic. This result was confirmed by two approaches: by the absence of a significant number of double-labeled cells following discrete horseradish peroxidase labeling of the DLF and by the persistence of double-labeled cells in animals with DLF lesions made rostral to intraspinal injections of horseradish peroxidase solutions. The conclusion is made that the previously described nucleus raphe magnus-DLF-dorsal horn pathway is predominantly non-serotonergic.

3,3'-Diaminobenzidine↗
PubMed1983

The neural basis of footshock analgesia: the role of specific ventral medullary nuclei.

Previous studies have demonstrated that brief front paw shock produces opiate analgesia while brief hind paw shock produces non-opiate analgesia in rats. Additionally, front paw shock and hind paw shock can produce an opiate-mediated classically conditioned analgesia; that is, when shock is delivered to an animal, environmental cues become associated with this stimulus such that these cues become capable of producing potent opiate analgesia in the absence of shock. Investigations of the neural bases of these phenomena have revealed that front paw shock and classical conditioning lead to activation of supraspinal sites which mediate analgesia via descending pathways lying solely within the dorsolateral funiculus (DLF) of the spinal cord. Hind paw footshock induced analgesia (FSIA) is also mediated by a descending DLF pathway but is unlike front paw FSIA or classically conditioned analgesia in that it involves intraspinal pathways as well. The aim of the present series of experiments was to identify the supraspinal origin of the centrifugal DLF pathway mediating front paw (opiate) FSIA, hind paw (non-opiate) FSIA, and classically conditioned (opiate) analgesia. These studies examined the effect of electrolytic lesions of the nucleus raphe magnus (NRM), nucleus reticularis paragigantocellularis (PGC), and combined lesions of these two areas (nucleus raphe alatus, NRA) on these environmentally-induced analgesias. The results of this work indicate that the NRA is the origin of the spinal cord DLF pathway mediating front paw (opiate) FSIA and classically conditioned (opiate) analgesia. Hind paw (non-opiate) FSIA is also mediated, in part, by the NRA but must involve another, yet unidentified, brainstem site(s) as well.

Analgesia↗
PubMed1983

The neural basis of footshock analgesia: the effect of periaqueductal gray lesions and decerebration.

Previous studies have demonstrated that brief front paw shock and brief hind paw shock produce potent opiate and non-opiate analgesia, respectively. Front paw footshock-induced analgesia (FSIA) and hind paw FSIA are similar in that each is mediated by a medullospinal pathway. A question which arises is whether these opiate and non-opiate descending pathways are activated in direct response to afferent information from the spinal cord or whether indirect activation via more rostral centers is required. The first experiment examined the effect of lesions of the rostral periaqueductal gray (PAG) and caudal PAG on front paw (opiate) FSIA and hind paw (non-opiate) FSIA. In no case did PAG lesions markedly reduce the magnitude of these pain inhibitory states. Since this result raised the possibility that rostral centers may not have any major involvement in the production of these phenomena, the second experiment examined the effect of decerebration on front paw FSIA and hind paw FSIA. Decerebration effect on hind paw FSIA and, at most, produced only a very modest decrease in front paw FSIA. The fact that potent and prolonged analgesia can still be elicited after decerebration clearly demonstrates that limbic, cortical, thalamic, and rostral midbrain structures are not critical to the production of these pain inhibitory effects. Thus this work provides the first demonstration of opiate and non-opiate analgesia systems within the caudal brainstem and spinal cord which can be activated by environmental stimuli.

Analgesia↗
PubMed1983

Opioid and non-opioid mechanisms of footshock-induced analgesia: role of the spinal dorsolateral funiculus.

Exposure to inescapable footshock causes either an opioid or non-opioid mediated analgesia in the rat depending on the temporal parameters of its administration. Lesions of the spinal dorsolateral funiculus significantly reduce both the opioid and non-opioid forms of this footshock-induced analgesia. Thus, these two neurochemically discrete pain-inhibitory systems appear to depend on the integrity of the same descending path, one known to be activated by morphine and by analgesic brain stimulation.

Analgesia↗
PubMed1983

Supramedullary afferents of the nucleus raphe magnus in the rat: a study using the transcannula HRP gel and autoradiographic techniques.

Afferents of the nucleus raphe magnus (NRM) were retrogradely labelled by using a transcannula HRP gel technique in conjunction with tetramethylbenzidine neurohistochemistry to determine the sources of inputs to the nucleus which could potentially influence the descending antiociceptive raphe-spinal system. Large numbers of HRP-labelled neurons were seen in the frontal cortex, dorsomedial nucleus of the hypothalamus, zona incerta, nucleus parafascicularis prerubralis (NPfPr), pretectum, dorsal and lateral periaqueductal gray, nucleus cuneiformis (NC), deep superior colliculus (dSC), a paraoculomotor cell group which may be the medial accessory nucleus of Bechterew, dorsal column nuclei, and spinal trigeminal nucleus. Smaller numbers of labelled cells were also observed in the preoptic area, nucleus of Darkschewitsch, ventral peri(third)ventricular gray, nucleus reticularis pontis oralis and caudalis, medial and lateral vestibular nuclei, and a subdivision of the hypoglossal nucleus. Confirmational anterograde autoradiographic studies were performed by injecting tritiated leucine into two of the principal sources of afferents to NRM: NPfPr, and dSC/NC. The results are compared with control HRP gel implants in the inferior olive, spinal cord, nucleus reticularis paragigantocellularis, and medial facial nucleus. Comments are also made concerning the parcellation of the ventromedial medulla and the possible role of both NRM and its afferents in central analgesic mechanisms.

Animals↗
PubMed1983

Evidence for the neuropeptide cholecystokinin as an antagonist of opiate analgesia.

The endogenous neuropeptide cholecystokinin, when administered systemically or perispinally, potently antagonizes opiate analgesia produced by foot shock and morphine. Nonopiate foot-shock analgesia is not reduced by this neuropeptide. The spinal cord appears to be a critical site of cholecystokinin action. These experiments suggest a physiological role for cholecystokinin as a specific opiate antagonist in analgesia-mediating systems. A similar mode of action may explain other behavioral effects of cholecystokinin, such as suppression of food intake.

Animals↗
PubMed1982

Footshock induced analgesia is dependent neither on pituitary nor sympathetic activation.

A variety of environmental stimuli have been demonstrated to produce behavioral analgesia. Of these, footshock has been shown to be capable of differentially eliciting opiate or non-opiate analgesia dependent upon the body region shocked; front paw and hind paw shock produce opiate and non-opiate analgesia, respectively. In addition, footshock can be used as a conditioned stimulus to elicit classically conditioned opiate analgesia. A question which arises is whether such plain inhibition is mediated by neural or hormonal pathways. Evidence exists which suggests that endogenous opioids in the pituitary and adrenal medulla may be involved in the production of environmentally induced analgesia. Furthermore, epinephrine administration has previously been shown to produce pronounced pain inhibition. However, the present series of experiments demonstrate that the pituitary-adrenal cortical and sympathetic-adrenal medullary axes are neither necessary nor sufficient for the production of footshock induced analgesia (FSIA). Hypophysectomy failed to attenuate front paw FSIA, hind paw FSIA or classically conditioned analgesia indicating that pituitary beta-endorphin or other pituitary factors are not necessary for the production of analgesia. Adrenal opioids and peripheral catecholamines are also not critical since front paw FSIA was potentiated by adrenalectomy or total sympathetic blockade. Furthermore, pituitary and sympathetic activation are not sufficient for the production of analgesia since low thoracic spinalization allows normal hormonal response to front paw shock yet abolishes shock-induced inhibition of the spinally mediated tail flick reflex. These results provide strong evidence that front paw FSIA, hind paw FSIA and classically conditioned analgesia are mediated by neural, rather than hormonal pathways and provide further parallels between these forms of environmental analgesia, morphine analgesia and brain stimulation produced analgesia.

Adrenalectomy↗
PubMed1982

Opiate vs non-opiate footshock induced analgesia (FSIA): descending and intraspinal components.

Opiate and non-opiate footshock induced analgesia (FSIA) can be differentially elicited dependent upon the body region shocked. As measured by the spinally-mediated tail flick test, hind paw shock produces non-opiate analgesia where front paw shock produces opiate analgesia. The present series of experiments utilized cord lesions and transections to identify descending and intraspinal pathways mediating front paw and hind paw FSIA. The results of these studies indicate that front paw shock leads to activation of supraspinal sites which mediate analgesia via descending pathways lying solely within the dorsolateral funiculus (DLF) of the spinal cord; direct intraspinal pathways are not involved. Hind paw FSIA is also mediated by a descending DLF pathway but is unlike front paw FSIA in that it involves intraspinal pathways as well. This work provides further parallels between the analgesias produced by morphine, electrical brain stimulation and environmental stimuli.

Analgesia↗
PubMed1982

Classical conditioning of front paw and hind paw footshock induced analgesia (FSIA): naloxone reversibility and descending pathways.

Opiate and non-opiate footshock induced analgesia (FSIA) has recently been observed to be differentially elicited dependent upon the body region shocked; front paw and hind paw shock produce opiate and non-opiate analgesia, respectively. Previous studies have shown that footshock can also produce classically conditioned analgesia; that is, when shock is delivered to an animal, environmental cues become associated with the noxious stimulus such that these cues become capable, in and of themselves, of producing potent analgesia. The present series of experiments examined analgesia classically conditioned to either front paw or hind paw shock. The non-electrified shock grid served as the conditioned stimulus (CS), 90-s footshock as the unconditioned stimulus (UCS) and tail-flick inhibition as the unconditioned response (UCR). Following CS-UCS pairings, exposure to the non-electrified grid reliably produced prolonged analgesia. This classically conditioned analgesia appears to involve endogenous opioids, regardless of the body region shocked during conditioning trials, since the analgesia is attenuated by systemic naloxone and shows cross-tolerance to morphine. A spinal opioid site is involved since 1 microgram of naloxone delivered directly to the lumbosacral cord antagonizes the analgesia. Like front paw (opiate) FSIA, CCA can be prevented but cannot be reversed by naloxone; naloxone can antagonize classically conditioned analgesia only if it is delivered prior to exposure to the conditioned stimulus. Lastly, a similarity was recognized between classically conditioned analgesia and the analgesia induced by morphine, brain stimulation, front paw shock and hind paw shock in that all are mediated via descending pathways within the dorsolateral funiculus of the spinal cord.

Analgesia↗