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Biomedical subjects

M M Morgan

Publications and source records attributed to M M Morgan.

At least 19 recordsLinked to original sources
PubMed2005

Evidence for an intrinsic mechanism of antinociceptive tolerance within the ventrolateral periaqueductal gray of rats.

Repeated microinjections of morphine into the ventrolateral periaqueductal gray produce antinociceptive tolerance. This tolerance may be a direct effect of morphine on cells within the ventrolateral periaqueductal gray or may require activation of downstream structures such as the rostral ventromedial medulla or spinal cord. Experiment 1 examined whether tolerance develops when opioid receptors in the ventrolateral periaqueductal gray are blocked prior to repeated systemic morphine administration. Microinjections of naltrexone hydrochloride (1microg/0.4microl) into the ventrolateral periaqueductal gray blocked antinociception and significantly attenuated the development of antinociceptive tolerance produced from systemic morphine administration. Experiment 2 examined whether tolerance develops when the effects of morphine are isolated to the ventrolateral periaqueductal gray. This was accomplished by microinjecting morphine (5microg/0.4microl) into the ventrolateral periaqueductal gray while simultaneously blocking the descending output through the rostral ventromedial medulla. Inhibition of neurons within the rostral ventromedial medulla by microinjecting the GABA(A) agonist muscimol (10ng/0.5microl) blocked the antinociception produced by microinjection of morphine into the ventrolateral periaqueductal gray but did not block the development of tolerance. These data demonstrate that the ventrolateral periaqueductal gray is both necessary and sufficient to produce tolerance to the antinociceptive effect of morphine. The ventrolateral periaqueductal gray is necessary in that tolerance does not develop if opiate action within the ventrolateral periaqueductal gray is blocked (experiment 1). The ventrolateral periaqueductal gray is sufficient in that tolerance occurs even when morphine's effects are restricted to the ventrolateral periaqueductal gray (experiment 2).

Analgesics↗
PubMed2004

Dissociation of hyperalgesia from fever following intracerebroventricular administration of interleukin-1beta in the rat.

Interleukin-1beta (IL-1beta) is a cytokine that contributes to the hyperalgesia, inactivity, and fever associated with illness. These three components of the illness response occur simultaneously following peripheral administration of IL-1beta. The objective of the present study was to determine whether hyperalgesia, inactivity, and fever correspond following central administration. Rats were injected with IL-1beta (0.05 pg-50 ng/10 microl) into the lateral ventricle and core body temperature and activity were assessed for 5.5 h using radio telemetry while rats remained in their home cage. Rats were removed from the cage periodically to assess nociception by measuring the latency for hindpaw withdrawal to radiant heat. The two highest doses of IL-1beta (5 and 50 ng) caused an increase in core body temperature and a decrease in activity beginning 105 min following administration. No change in nociception was evident at any time after administration of IL-1beta regardless of dose. These data indicate that the hyperalgesia associated with fever is triggered by a peripheral, not a central action of IL-1beta, presumably by activation of vagal afferents.

Animals↗
PubMed2004

Oestradiol dampens reflex-related activity of on- and off-cells in the rostral ventromedial medulla of female rats.

The present study was conducted to determine whether the ovarian steroid oestradiol alters the activity of nociceptive modulatory neurons in the rostral ventromedial medulla (RVM). Adult female rats were ovariectomized and implanted s.c. with an oestradiol-filled or placebo capsule. Sixteen to 37 days later, rats were anaesthetised for single unit recording from RVM neurons. On-cells were characterised by a burst of activity, and off-cells by a pause in activity immediately preceding reflexive withdrawal of the tail from 51 and 54 degrees C water. Although on- and off-cells were evident in both oestradiol- and placebo-treated rats, the reflex-related on-cell burst and off-cell pause were dampened in oestradiol-treated rats. On-cells from oestradiol-treated rats had a mean activity burst of 9.1+/-2.2 Hz in the 2 s preceding the tail withdrawal reflex to 51 degrees C water, compared with 17.9+/-4.3 Hz for on-cells in placebo controls. Off-cell activity during the 2 s preceding tail withdrawal was 4.8+/-2.2 vs. 0.1+/-0.1 Hz in oestradiol vs. placebo-treated females, respectively. Similar changes in on- and off-cell activity occurred when the tail was placed in 54 degrees C water. The present data demonstrate that oestradiol constrains the magnitude of the shift in RVM on- and off-cell activity associated with nociceptive reflexes.

Animals↗
PubMed2004

Behavioral and electrophysiological evidence for tolerance to continuous morphine administration into the ventrolateral periaqueductal gray.

Repeated microinjections of morphine into the ventrolateral periaqueductal gray (vPAG) produce tolerance to the antinociceptive effect of morphine [Behav Neurosci 113 (1999) 833]. These results may be a direct effect of morphine on cells within the vPAG or be caused by cues linked to the microinjection procedure (i.e. associative tolerance). The objective of this paper was to determine whether continuous administration of morphine into the vPAG (i.e. no cues) would produce tolerance. Tolerance was assessed by measuring changes in behavior and changes in the activity of neurons in the rostral ventromedial medulla (RVM), the primary output target of the PAG. Rats were implanted with an osmotic minipump that released morphine (2.5 or 5 microg/h) or saline into the vPAG continuously. Continuous administration of morphine produced an increase in hotplate latency when measured 6 h after initiation of treatment. Tolerance to this antinociception was evident within 24 h. After 3 days, rats were anesthetized and the activity of RVM neurons was assessed. Although acute morphine administration into the RVM inhibits the activity of RVM on-cells and enhances the activity of off-cells, these neurons appeared normal following 3 days of continuous morphine administration. Systemic naloxone administration produced hyperalgesia that was associated with a marked increase in on-cell activity and a complete cessation of off-cell activity. The loss of morphine inhibition of nociception, measured behaviorally and electrophysiologically, demonstrates that tolerance is caused by a direct action of morphine on vPAG neurons.

Analgesics, Opioid↗
PubMed2003

Behavioral evidence linking opioid-sensitive GABAergic neurons in the ventrolateral periaqueductal gray to morphine tolerance.

Tolerance develops to the antinociceptive effects of morphine with repeated microinjections into the ventrolateral periaqueductal gray (PAG). This tolerance could be caused by adaptations within the PAG or anywhere along the descending pathway (rostral ventromedial medulla to spinal cord). If tolerance is caused by a change along the descending pathway, then tolerance should develop to direct activation of PAG output neurons. However, if tolerance is caused by a change to neurons within the PAG, then tolerance will not occur with repeated direct activation of PAG output neurons. This hypothesis was tested by assessing antinociception following repeated microinjections of the GABA antagonist bicuculline and the excitatory amino acid kainate into the ventrolateral PAG. Microinjection of bicuculline and kainate produces antinociception by disinhibition and direct excitation of ventrolateral PAG output neurons, respectively. Repeated administration of these drugs into the ventrolateral PAG produced antinociception with no evidence of tolerance. That is, the hot-plate latency and responsiveness to intraplantar formalin administration was comparable whether rats received the drug for the first or fifth time. Moreover, microinjection of bicuculline or kainate produced comparable antinociception in rats pretreated with these drugs and saline-treated control rats. These data demonstrate that repeated activation of ventrolateral PAG output neurons is not sufficient to produce tolerance. Thus, tolerance must be caused by a change in neurons preceding output neurons in this circuit, presumably opioid-sensitive GABAergic neurons.

Analgesics, Opioid↗
PubMed2002

Comparison of morphine and kainic acid microinjections into identical PAG sites on the activity of RVM neurons.

The rostral ventromedial medulla (RVM) modulates nociception through changes in the activity of two classes of neuron, ON- and OFF-cells. The activity of these neurons is regulated, in part, by input from the periaqueductal gray (PAG). The objective of this study was to determine whether PAG-mediated antinociception is associated with excitation of both ON- and OFF-cells in the RVM. Microinjection of morphine into the ventrolateral PAG produced antinociception at 50% of the injection sites. This antinociception was associated with continuous activation of RVM OFF-cells and inhibition of both the spontaneous and reflex-related activity of RVM ON-cells. Microinjection of kainic acid into the same injection sites produced antinociception 92% (37/40) of the time. Although kainic acid directly excites PAG output neurons, the changes in ON- and OFF-cell activity associated with microinjection of kainic acid into the ventrolateral PAG were the same as when morphine was injected. That is, ON-cells were inhibited and OFF-cells were activated. These data indicate that the excitatory connection between the PAG and RVM is directed at RVM OFF-cells specifically. In addition, these data suggest that direct activation of PAG output neurons, as occurs with kainic acid, is much more likely to produce antinociception than disinhibition of output neurons as occurs following morphine administration.

Analgesics, Opioid↗
PubMed2001

Superantigen-induced T cell:B cell conjugation is mediated by LFA-1 and requires signaling through Lck, but not ZAP-70.

The formation of a conjugate between a T cell and an APC requires the activation of integrins on the T cell surface and remodeling of cytoskeletal elements at the cell-cell contact site via inside-out signaling. The early events in this signaling pathway are not well understood, and may differ from the events involved in adhesion to immobilized ligands. We find that conjugate formation between Jurkat T cells and EBV-B cells presenting superantigen is mediated by LFA-1 and absolutely requires Lck. Mutations in the Lck kinase, Src homology 2 or 3 domains, or the myristoylation site all inhibit conjugation to background levels, and adhesion cannot be restored by the expression of Fyn. However, ZAP-70-deficient cells conjugate normally, indicating that Lck is required for LFA-1-dependent adhesion via other downstream pathways. Several drugs that inhibit T cell adhesion to ICAM-1 immobilized on plastic, including inhibitors of mitogen-activated protein/extracellular signal-related kinase kinase, phosphatidylinositol-3 kinase, and calpain, do not inhibit conjugation. Inhibitors of phospholipase C and protein kinase C block conjugation of both wild-type and ZAP-70-deficient cells, suggesting that a phospholipase C that does not depend on ZAP-70 for its activation is involved. These results are not restricted to Jurkat T cells; Ag-specific primary T cell blasts behave similarly. Although the way in which Lck signals to enhance LFA-1-dependent adhesion is not clear, we find that cells lacking functional Lck fail to recruit F-actin and LFA-1 to the T cell:APC contact site, whereas ZAP-70-deficient cells show a milder phenotype characterized by disorganized actin and LFA-1 at the contact site.

B-Lymphocytes↗
PubMed2001

Tolerance to repeated microinjection of morphine into the periaqueductal gray is associated with changes in the behavior of off- and on-cells in the rostral ventromedial medulla of rats.

Although the administration of opioids is the most effective treatment for pain, their efficacy is limited by the development of tolerance. The midbrain periaqueductal gray matter (PAG) participates in opioid analgesia and tolerance. Microinjection of morphine into PAG produces antinociception, probably through neurons in the rostral ventromedial medulla (RVM), namely through the activation of off-cells, which inhibit nociception, and the inhibition of on-cells, which facilitate nociception. After its repeated microinjection into the PAG morphine loses effectiveness. The present study sought to determine whether tolerance to PAG morphine administration is associated with changes in the behavior of RVM neurons. Morphine (0.5 microg/0.4 microl) or saline (0.4 microl) was microinjected into the ventrolateral PAG twice daily. Initially morphine caused a latency increase in the hot plate test (antinociception) but this effect disappeared by day 3 (tolerance). On day 4, each rat was anesthetized with halothane and recordings were made from off- and on-cells in the RVM, i.e. from neurons that decrease or increase their firing, respectively, just before a heat-elicited tail flick. In contrast to saline-pretreated rats, PAG microinjection of morphine in tolerant animals did not change the baseline activity of off- or on-cells, did not prevent the off-cell pause or the on-cell activation upon tail heating, and did not lengthen the tail flick latency. However, microinjection of kainic acid into the PAG (1) caused off-cells to become continuously active and on-cells to become silent, and (2) prevented the tail flick, i.e. exactly what morphine did before tolerance developed. These results demonstrate a correspondence between neuronal and behavioral measures of tolerance to PAG opioid administration, and suggest that tolerance is mediated by a change in opioid-sensitive neurons within the PAG.

Analgesics, Opioid↗
PubMed2001

Activation of the ventrolateral periaqueductal gray reduces locomotion but not mean arterial pressure in awake, freely moving rats.

Activation of the ventrolateral periaqueductal gray produces immobility and antinociception. It has been argued that these behaviors are part of either a defensive fear response to threat or a recuperative quiescence response to deep tissue injury. Data collected in anesthetized animals showing that activation of the ventrolateral periaqueductal gray has a hypotensive effect supports the quiescence hypothesis. Our objective was to determine whether activation of the ventrolateral periaqueductal gray in awake, freely moving rats results in a decrease in blood pressure as it does in anesthetized animals. Changes in blood pressure produced by microinjection of the neuroexcitant D,L-homocysteic acid were measured using radio telemetry while rats were awake and while anesthetized with pentobarbital. Consistent with earlier reports, microinjection of D,L-homocysteic acid into the ventrolateral periaqueductal gray caused a decrease in blood pressure in anesthetized rats. In contrast, microinjection at the same ventrolateral periaqueductal gray sites while rats were awake had no effect on blood pressure, even though the animals became immobile and heart rate decreased. Thus, the immobility evoked from ventrolateral periaqueductal gray is not associated with a fall in mean arterial pressure. Two conclusions can be drawn from these data. (1) Caution must be used in generalizing from data collected in anesthetized animals. (2) The ventrolateral periaqueductal gray is as likely to contribute to defensive fear as to recuperative quiescence.

Animals↗
PubMed2001

GAPS between MFT supervision assumptions and common practice: suggested best practices.

This article summarizes gaps between assumptions that appear in the literature, research, and accepted standards for marital and family therapy (MFT) supervision, and the common practice of supervisors. Issues that stem from these gaps are highlighted and recommendations are made for closing them. In an effort to refine the standard of practice for MFT supervision, best practice recommendations are offered for MFT supervision.

Ethics, Professional↗
PubMed2000

Immobility accompanies the antinociception mediated by the rostral ventromedial medulla of the rat.

The rostral ventromedial medulla (RVM) is part of a descending pain modulatory system that runs from the periaqueductal gray (PAG) to the spinal cord. The objective of the present study was to determine whether the antinociception mediated by the RVM is associated with locomotor changes as has been reported for the PAG [42]. Kainate (4, 20, or 40 pmol), morphine (1, 5, or 10 microg), or saline (0.2 or 0. 5 microl) was injected into the RVM and locomotion and nociception assessed. Microinjections of kainate and morphine that produced antinociception almost invariably inhibited locomotor activity. In some rats this immobility consisted of no movements when placed in the center of the open field chamber. These data are consistent with the immobility and antinociception produced by activation of the ventrolateral PAG and indicate that the descending ventrolateral PAG/RVM system integrates a behavioral response of which antinociception is only one component.

Analgesics↗
PubMed1999

TCR, LFA-1, and CD28 play unique and complementary roles in signaling T cell cytoskeletal reorganization.

T cells interacting with APCs undergo rearrangement of surface receptors and cytoskeletal elements to face the zone of contact with the APC. This polarization process is thought to affect T cell signaling by organizing a specialized domain on the T cell surface and to direct T cell effector function toward the appropriate APC. We have investigated the contribution of TCR, CD28, and LFA-1 signaling to T cell cytoskeletal polarization by assaying the response of an Ag-specific Th1 clone toward a panel of transfected APCs expressing MHC class II alone or in combination with ICAM-1 or B7-1. We show that polarization of talin, an actin-binding protein, occurs in response to integrin engagement. In contrast, reorientation of the T cell microtubule-organizing center (MTOC) is dependent on and directed toward the site of TCR signaling, regardless of whether integrins or costimulatory molecules are engaged. MTOC reorientation in response to peptide-MHC complexes is sensitive to the phosphatidylinositol 3-kinase inhibitor wortmannin. CD28 coengagement overcomes this sensitivity, as does activation via Ab cross-linking of the TCR or via covalent peptide-MHC complexes, suggesting that phosphatidylinositol 3-kinase is not required per se but rather plays a role in signal amplification. Engagement of TCR in trans with LFA-1 results in separation of MTOC reorientation and cortical cytoskeletal polarization events, indicating that the two processes are not directly mechanistically linked. These studies show that T cells mobilize individual cytoskeletal components in response to distinct and specific cell surface interactions.

Actins↗
PubMed1999

Paradoxical inhibition of nociceptive neurons in the dorsal horn of the rat spinal cord during a nociceptive hindlimb reflex.

Nociceptive-specific and multireceptive neurons in the lumbar dorsal horn are excited by noxious stimuli applied to the hindpaw and inhibited by noxious stimuli applied to distant body regions. Given that at least a subset of these neurons are part of the circuit for nociceptive reflexes, inhibition of nociceptive-specific and multireceptive neurons should inhibit nociceptive reflexes. Unfortunately, previous attempts to test this hypothesis have been inconclusive because of methodological differences between electrophysiological and behavioral experiments. The present study overcame this problem by recording neural and reflex activity simultaneously. Rats were anesthetized with halothane and surgically prepared for single-unit recording from the lumbar dorsal horn. Hindpaw heat caused a burst of activity that reliably preceded hindpaw withdrawal in 10 nociceptive-specific and 17 multireceptive neurons. A distant noxious stimulus (tail in 50 degrees C water or ear pinch) inhibited the evoked activity of both nociceptive-specific and multireceptive neurons and simultaneously changed the topography of the hindpaw reflex from flexion to extension without altering reflex latency. The present data are consistent with previous reports of inhibition of nociceptive-specific and multireceptive neurons during application of a distant noxious stimulus. However, inhibition of nociceptive-specific and multireceptive neurons concomitant with a shift in the hindlimb reflex from flexion to extension suggests that these neurons are part of the circuit for flexor reflexes specifically. Presumably, lateral inhibition from the flexor to extensor circuit allows for the release of hindlimb extension when neurons in the flexion circuit are inhibited by a distant noxious stimulus. Such a system reduces the chance of injury by allowing for withdrawal reflexes to a single noxious stimulus and escape reactions, such as running and jumping, to multiple noxious stimuli.

Action Potentials↗
PubMed1999

Tolerance to the antinociceptive effect of morphine microinjections into the ventral but not lateral-dorsal periaqueductal gray of the rat.

Tolerance to the antinociceptive effect of morphine is mediated at least in part by morphine's action within the periaqueductal gray (PAG). The objective of the present study was to determine whether both ventral and lateral-dorsal PAG regions contribute to the development of tolerance. It was found that the antinociceptive efficacy of microinjecting morphine (5 microg/0.4 microl) into the ventral but not the lateral-dorsal PAG diminished with successive injections. Control experiments indicated that this decrease was caused by tolerance to morphine and was not a result of cell death caused by repeated microinjections or habituation from repeated behavioral testing. The finding of greater susceptibility of the ventral compared with the lateral-dorsal PAG to the development of tolerance adds to a growing literature distinguishing antinociception from these two regions.

Analgesics, Opioid↗
PubMed1999

Optimizing healthcare research data warehouse design through past COSTAR query analysis.

Over the past two years we have reviewed and implemented the specifications for a large relational database (a data warehouse) to find research cohorts from data similar to that contained within the clinical COSTAR database at the Massachusetts General Hospital. A review of 16 years of COSTAR research queries was conducted to determine the most common search strategies. These search strategies are relevant to the general research community, because they use the Medical Query Language (MQL) developed for the COSTAR M database which is extremely flexible (much more so than SQL) and allows searches by coded fields, text reports, and laboratory values in a completely ad hoc fashion. By reviewing these search strategies, we were able to obtain user specifications for a research oriented healthcare data warehouse that could support 90% of the queries. The data warehouse was implemented in a relational database using the star schema, allowing for highly optimized analytical processing. This allowed queries that performed slowly in the M database to be performed very rapidly in the relational database. It also allowed the data warehouse to scale effectively.

Databases as Topic↗
PubMed1998

Immobility and flight associated with antinociception produced by activation of the ventral and lateral/dorsal regions of the rat periaqueductal gray.

It has long been known that the periaqueductal gray (PAG) plays an important role in the modulation of nociception. Given that activation of the lateral PAG also produces wild running and tachycardia, it has been suggested that PAG mediated antinociception is part of an integrated defensive reaction. However, an alternative hypothesis is that these effects are merely a secondary response to aversive brain stimulation. If antinociception and flight reactions are caused by aversive brain stimulation, then these effects should always occur together. The objective of the present study was to determine whether antinociception and locomotion could be dissociated by microinjecting morphine and kainic acid into various subdivisions of the caudal PAG. Non-selective activation of lateral and dorsal regions of the PAG by microinjection of kainic acid produced wild running, while injections into the ventrolateral PAG produced immobility. Microinjection of morphine evoked similar locomotor effects, although the onset to effect was slower with morphine (approximately 5 min vs. 1 min for kainic acid), and the antinociceptive efficacy of microinjecting 0.2 microl of morphine was less than with kainic acid injections. In fact, microinjection of morphine evoked locomotor effects in the absence of antinociception on 39% of the tests. Increasing the injection volume to 0.4 microl (dose remained at 5 microg) greatly enhanced the likelihood that antinociception and locomotor effects (e.g. running, freezing, circling) occurred simultaneously (79%). These findings indicate that, although distinct locomotor effects are associated with antinociception from the ventral and more dorsal regions of the PAG, antinociceptive and locomotor effects can occur independently. This finding is consistent with the hypothesis that ventral and dorsal regions of the PAG integrate defensive freezing and flight reactions, respectively.

Animals↗
PubMed1998

Microinjection of morphine into the rostral ventromedial medulla produces greater antinociception in male compared to female rats.

The antinociceptive and locomotor effects of microinjecting morphine into the rostral ventromedial medulla (RVM) of male and female rats was assessed. Male rats showed greater antinociception than female rats at all doses and times following morphine administration. Male, but not female rats, also showed a dose dependent decrease in locomotion. These data demonstrate that sex differences in antinociception are mediated at least in part by the RVM.

Animals↗