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K A Keay

Publications and source records attributed to K A Keay.

At least 19 recordsLinked to original sources
PubMed2005

Enhanced Fos expression in glutamic acid decarboxylase immunoreactive neurons of the mouse periaqueductal grey during opioid withdrawal.

Previous studies using c-Fos immunohistochemistry suggest that a sub-population of neurons in the midbrain periaqueductal gray region is activated during opioid withdrawal. The neurochemical identity of these cells is unknown but cellular physiological studies have implicated GABAergic neurons. The present study investigated whether GABAergic neurons are activated in the mouse periaqueductal gray during opioid withdrawal using dual-antibody immunohistochemistry for Fos and glutamic acid decarboxylase. Both chronic opioid treatment and naloxone-precipitated opioid withdrawal increased Fos expression in the periaqueductal gray, with the greatest increase being four-fold in the caudal ventrolateral subdivision following withdrawal. Neurons stained for both Fos and glutamic acid decarboxylase were greatly enhanced in all subdivisions of the periaqueductal gray following withdrawal, particularly in the lateral and ventrolateral divisions where the increase was up to 70-fold. These results suggest that activation of a subpopulation of GABAergic interneurons in the periaqueductal gray plays a role in opioid withdrawal.

Animals↗
PubMed2003

Haemodynamic response to haemorrhage: distinct contributions of midbrain and forebrain structures.

The haemodynamic response to a fixed volume haemorrhage passes through three distinct phases: a normotensive, compensatory phase; a hypotensive, decompensatory phase; and a post-haemorrhage, recompensatory phase. The role of the forebrain and midbrain in regulating the triphasic response to a 'fast' (1.5%/min) or 'slow' (0.75%/min) rate of blood withdrawal (30% haemorrhage) was evaluated by comparing, in unanaesthetised rats, the effects of pre-collicular (PCD) vs. pre-trigeminal decerebrations (PTD). It was found that pre-trigeminal decerebration attenuated the decompensatory (hypotensive) phase to either a fast or slow haemorrhage. In contrast, pre-collicular decerebration attenuated the compensatory and recompensatory phases of the response to a 'fast' (but not a slow) haemorrhage. These results suggest that the integrity of (i) forebrain structure(s) are critical for compensatory and recompensatory responses to 'rapid' blood loss; and (ii) midbrain structure(s) are critical for the decompensatory response to progressive blood loss irrespective of rate.

Animals↗
PubMed2002

Noxious activation of spinal or vagal afferents evokes distinct patterns of fos-like immunoreactivity in the ventrolateral periaqueductal gray of unanaesthetised rats.

The consequences of a severe traumatic injury--deep pain and haemorrhage--usually evoke a passive emotional coping reaction characterised by: quiescence and immobility, decreased vigilance, hypotension and bradycardia. Results of studies utilising microinjections of excitatory amino acids suggest that passive coping reactions are mediated, at least in part, by activation of the midbrain, ventrolateral periaqueductal gray (vlPAG) region. Further, experiments in anaesthetised rats, using the expression of the immediate-early gene, c-fos, as a marker of neuronal activation, report that pain arising from muscles, joints or viscera selectively activates the vlPAG. Anaesthesia alone, however, evokes substantial Fos-like immunoreactivity (IR) within the vlPAG and this may have obscured any differences in patterns of Fos expression following noxious deep somatic versus noxious visceral activation. In these experiments, in unanaesthetised rats, the effects of noxious spinal versus noxious vagal primary afferent activation were re-examined and distinct rostrocaudal patterns of Fos-expression were observed. Specifically: (i) injection of algesic substances into muscle, which preferentially activates spinal afferents, evoked Fos expression predominantly within the caudal vlPAG; whereas, (ii) noxious manipulations whose effects are mediated by (cardiopulmonary) vagal activation evoked preferential Fos-expression within the rostral vlPAG. On the other hand, hypotensive haemorrhage evoked substantial Fos expression along the entire rostrocaudal extent of the vlPAG, a finding which fits with suggestions that haemorrhagic shock is triggered by a combination of: (i) spinally-relayed nociceptive signals originating from ischaemic tissue, and (ii) vagally-relayed signals reflecting poor cardiac filling.

Afferent Pathways↗
PubMed2002

Haemorrhage-evoked compensation and decompensation are mediated by distinct caudal midline medullary regions in the urethane-anaesthetised rat.

Previous research using microinjections of excitatory amino acids suggested that the caudal midline medulla (including nucleus raphe obscurus and nucleus raphe pallidus) contained a mixed population of sympathoexcitatory and sympathoinhibitory neurones. The results of this study indicate that different anaesthetic regimes (urethane versus halothane) determine whether sympathoexcitatory (urethane only) or sympathoinhibitory (halothane only) responses are evoked by stimulation within distinct caudal midline medullary regions. In addition, anaesthetic regimes also affect the caudal midline medullary-mediated response to haemorrhage. Specifically, under conditions of urethane anaesthesia, inactivation (lignocaine) of the midline medullary region immediately caudal to the obex, prematurely triggered and dramatically potentiated the hypotension and bradycardia evoked by 15% haemorrhage; whereas under halothane anaesthesia, inactivation of the same region had no effect. In contrast, under urethane anaesthesia, inactivation of the midline medullary region immediately rostral to the obex, delayed the onset of the hypotension and bradycardia to 15% haemorrhage; inactivation of the same region under halothane anaesthesia blocked haemorrhage-evoked hypotension and bradycardia. Our findings indicate that topographically distinct parts of the caudal midline medulla contain neurones (i) that differentially regulate the timing and magnitude of the compensatory (normotensive) versus decompensatory (hypotensive) phases of the response to haemorrhage; and (ii) whose activity is altered by urethane versus halothane anaesthesia.

Anesthetics, Inhalation↗
PubMed2001

Different representations of inescapable noxious stimuli in the periaqueductal gray and upper cervical spinal cord of freely moving rats.

Previous work suggested that pain of distinct tissue origins was differentially represented in the midbrain periaqueductal gray (PAG). That is, persistent pain of deep origin (muscle, joint viscera) "activated" ventrolateral PAG neurons and triggered quiescence, hyporeactivity and vasodepression (i.e. passive emotional coping); whereas intermittent cutaneous pain "activated" lateral PAG neurons and triggered fight-flight (i.e. active emotional coping). Cutaneous noxious stimuli, if inescapable however, trigger a passive emotional coping reaction similar to that evoked by pain of deep origin. This raised the question--is it the behavioural significance (escapability versus inescapability) or the tissue origin (cutaneous versus deep) of the pain, that is represented in the PAG? In this study we used immediate-early-gene (c-Fos) expression to examine PAG and spinal activation patterns following "inescapable" (persistent) pain of cutaneous versus deep origin. It was found that selective activation of the ventrolateral PAG and passive emotional coping were evoked by an inescapable cutaneous noxious stimulus (i.e. clip of the neck), as well as by a deep noxious stimulus (i.e. neck muscle pain). In the upper cervical spinal cord, however, these noxious manipulations evoked distinct patterns of Fos expression which reflected the different patterns of primary afferent termination arising from skin versus muscle. The results suggest that whereas pain representation in the spinal cord accurately reflects tissue origin, pain representation in the PAG better reflects behavioural significance.

Animals↗
PubMed2001

Orbitomedial prefrontal cortical projections to hypothalamus in the rat.

A previous study in the rat revealed that distinct orbital and medial prefrontal cortical (OMPFC) areas projected to specific columns of the midbrain periaqueductal gray region (PAG). This study used anterograde tracing techniques to define projections to the hypothalamus arising from the same OMPFC regions. In addition, injections of anterograde and retrograde tracers were made into different PAG columns to examine connections between hypothalamic regions and PAG columns projected upon by the same OMPFC regions. The most extensive patterns of hypothalamic termination were seen after injection of anterograde tracer in prelimbic and infralimbic (PL/IL) and the ventral and medial orbital (VO/MO) cortices. Projections from rostral PL/IL and VO/MO targeted the rostrocaudal extent of the lateral hypothalamus, as well as lateral perifornical, and dorsal and posterior hypothalamic areas. Projections arising from caudal PL/IL terminated within the dorsal hypothalamus, including the dorsomedial nucleus and dorsal and posterior hypothalamic areas. There were also projections to medial perifornical and lateral hypothalamic areas. In contrast, it was found that anterior cingulate (AC), dorsolateral orbital (DLO), and agranular insular (AId) cortices projected to distinct and restricted hypothalamic regions. Projections arising from AC terminated within dorsal and posterior hypothalamic areas, whereas DLO and AId projected to the lateral hypothalamus. The same OMPFC regions also projected indirectly, by means of specific PAG columns, to many of the same hypothalamic fields. In the context of our previous findings, these data indicate that, in both rat and macaque, parallel but distinct circuits interconnect OMPFC areas with specific hypothalamic regions, as well as PAG columns.

Animals↗
PubMed2001

Parallel circuits mediating distinct emotional coping reactions to different types of stress.

All animals, including humans, react with distinct emotional coping strategies to different types of stress. Active coping strategies (e.g. confrontation, fight, escape) are evoked if the stressor is controllable or escapable. Passive coping strategies (e.g. quiescence, immobility, decreased responsiveness to the environment) are usually elicited if the stressor is inescapable and help to facilitate recovery and healing. Neural substrates mediating active versus passive emotional coping have been identified within distinct, longitudinal neuronal columns of the midbrain periaqueductal gray (PAG) region. Active coping is evoked by activation of either the dorsolateral or lateral columns of the PAG; whereas passive coping is triggered by activation of the ventrolateral PAG. Recent anatomical studies indicate that each PAG column receives a distinctive set of ascending (spinal and medullary) and descending (prefrontal cortical and hypothalamic) afferents. Consistent with the anatomy, functional studies using immediate early gene expression (c-fos) as a marker of neuronal activation have revealed that the preferential activation of a specific PAG column reflects (i) the type of emotional coping reaction triggered, and (ii) whether a physical or psychological stressor was used.

Adaptation, Psychological↗
PubMed2000

Spinal sources of noxious visceral and noxious deep somatic afferent drive onto the ventrolateral periaqueductal gray of the rat.

Studies utilizing the expression of Fos protein as a marker of neuronal activation have revealed that pain of deep somatic or visceral origin selectively activates the ventrolateral periaqueductal gray (vlPAG). Previous anatomical tracing studies revealed that spinal afferents to the vlPAG arose from the superficial and deep dorsal horn and nucleus of the dorsolateral funiculus at all spinal segmental levels, with approximately 50% of vlPAG-projecting spinal neurons found within the upper cervical spinal cord. This study utilized detection of Fos protein to determine the specific populations of vlPAG-projecting spinal neurons activated by noxious deep somatic or noxious visceral stimulation. Pain of cardiac or peritoneal (i.e., visceral) origin activated neurons in the superficial and deep dorsal horn and nucleus of the dorsolateral funiculus of the thoracic cord, whereas pain of hindlimb (i.e., deep somatic) origin activated neurons in the same laminar regions but in the lumbosacral cord. Each of these deep noxious manipulations also activated neurons in the superficial and deep dorsal horn and nucleus of the dorsolateral funiculus of the upper cervical spinal cord. In a second set of experiments, the combination of retrograde tracing and Fos immunohistochemistry revealed that vlPAG-projecting spinal neurons activated by deep somatic pain were located in both the upper cervical and lumbosacral cord, whereas those activated by visceral pain were restricted to the thoracic spinal cord. Thus pain arising from visceral versus deep somatic body regions influences neural activity within the vlPAG via distinct spinal pathways. The findings also highlight the potential significance of the upper cervical cord in integrating pain arising from deep structures throughout the body.

Afferent Pathways↗
PubMed2000

Muscle pain activates a direct projection from ventrolateral periaqueductal gray to rostral ventrolateral medulla in rats.

Activation of the ventrolateral periaqueductal gray (vlPAG) evokes a reaction of quiescence, immobility, hypotension and bradycardia. Pain of deep somatic or visceral origin also often triggers a reaction of quiescence, immobility, hypotension and bradycardia and further, evokes a selective increase in immediate-early-gene (c-Fos) expression within the vlPAG. Vasodepression evoked from the vlPAG is thought to be mediated by an inhibition of presympathetic neurons within the rostral ventrolateral medulla (RVLM). In this study the prior injection of retrograde tracer into the RVLM was combined with the use of Fos expression as a marker of neuronal activation, to determine if deep (muscle) pain-evoked vasodepression could be mediated by a direct vlPAG-RVLM pathway. It was revealed that intramuscular injection of formalin, in the anaesthetised rat, evoked a significant increase in Fos expression within the caudal vlPAG, and that approximately 25% of the Fos-immunoreactive neurons projected to the RVLM.

Animals↗
PubMed2000

Central circuits mediating patterned autonomic activity during active vs. passive emotional coping.

Animals, including humans, react with distinct emotional coping strategies to different sets of environmental demands. These strategies include the capacity to affect appropriate responses to "escapable" or "inescapable" stressors. Active emotional coping strategies--fight or flight--are particularly adaptive if the stress is escapable. On the other hand, passive emotional coping strategies-quiescence, immobility, decreased responsiveness to the environment-are useful when the stress is inescapable. Passive strategies contribute also to facilitating recovery and healing once the stressful event is over. Active vs. passive emotional coping strategies are characterised further by distinct patterns of autonomic change. Active strategies are associated with sympathoexcitation (hypertension, tachycardia), whereas passive strategies are associated with sympathoinhibitory patterns (hypotension, bradycardia). Distinct neural substrates mediating active vs. passive emotional coping have been identified within the longitudinal neuronal columns of the midbrain periaqueductal gray region (PAG). The PAG offers then a potentially useful point of entry for delineating neural circuits mediating the different forms of emotional coping and their associated patterns of autonomic activity. As one example, recent studies of the connections of orbital and medial prefrontal cortical (PFC) fields with specific PAG longitudinal neuronal columns are reviewed. Findings of discrete orbital and medial PFC projections to different PAG columns, and related PFC and PAG columnar connections with specific subregions of the hypothalamus, suggest that distinct but parallel circuits mediate the behavioural strategies and patterns of autonomic activity characteristic of emotional "engagement with" or "disengagement from" the external environment.

Adaptation, Psychological↗
PubMed2000

Orbitomedial prefrontal cortical projections to distinct longitudinal columns of the periaqueductal gray in the rat.

We utilised retrograde and anterograde tracing procedures to study the origin and termination of prefrontal cortical (PFC) projections to the periaqueductal gray (PAG) in the rat. A previous study, in the primate, had demonstrated that distinct subgroups of PFC areas project to specific PAG columns. Retrograde tracing experiments revealed that projections to dorsolateral (dlPAG) and ventrolateral (vlPAG) periaqueductal gray columns arose from medial PFC, specifically prelimbic, infralimbic, and anterior cingulate cortices. Injections made in the vlPAG also labeled cells in medial, ventral, and dorsolateral orbital cortex and dorsal and posterior agranular insular cortex. Other orbital and insular regions, including lateral and ventrolateral orbital, ventral agranular insular, and dysgranular and granular insular cortex did not give rise to appreciable projections to the PAG. Anterograde tracing experiments revealed that the projections to different PAG columns arose from specific PFC areas. Projections from the caudodorsal medial PFC (caudal prelimbic and anterior cingulate cortices) terminated predominantly in dlPAG, whereas projections from the rostroventral medial PFC (rostral prelimbic cortex) innervated predominantly the vlPAG. As well, consistent with the retrograde data, projections arising from select orbital and agranular insular cortical areas terminated selectively in the vlPAG. The results indicate: (1) that rat orbital and medial PFC possesses an organisation broadly similar to that of the primate; and (2) that subdivisions within the rat orbital and medial PFC can be recognised on the basis of projections to distinct PAG columns.

Animals↗
PubMed2000

Caudal midline medulla mediates behaviourally-coupled but not baroreceptor-mediated vasodepression.

Within the caudal medulla there are two regions whose activation leads to vasodepression and bradycardia, the caudal ventrolateral medulla and a discrete region of the caudal midline medulla. This study investigated, in the halothane anaesthetized rat, the contribution of these two vasodepressor regions to "homeostatic" and "behaviourally-coupled" cardiovascular regulation. In an initial set of experiments the contribution of each of these two regions to the hypotension and bradycardia evoked by acute hypovolaemia (15% haemorrhage) was investigated. It was found that inactivation of the caudal midline medulla significantly attenuated (cobalt chloride) or completely blunted (lignocaine) the hypotension and bradycardia evoked by acute hypovolaemia. In contrast, inactivation of the caudal ventrolateral medulla using cobalt chloride, although attenuating the magnitude of the hypotension and completely blocking the bradycardia, did not delay the onset of the hypotension evoked by acute hypovolaemia. The caudal ventrolateral medulla is known to be critical in homeostatic cardiovascular control through the expression of the "baroreceptor reflex" and the hypotension and bradycardia evoked by activation of cardiopulmonary afferents. In a second series of experiments we found inactivation of the caudal midline medulla played no role in baroreflex-evoked bradycardia (i.v. phenylephrine) or the hypotension and bradycardia evoked by cardiopulmonary afferent activation (i.v. 5-hydroxytryptamine). These data suggest that the caudal midline medulla and caudal ventrolateral medulla play different roles in cardiovascular control. The caudal ventrolateral medulla is involved in mediating cardiovascular changes associated with a variety of stimuli including "homeostatic" and "behaviourally-coupled" cardiovascular changes, whereas the caudal midline medulla is critical for mediating "behaviourally-coupled" changes in arterial pressure and heart rate.

Animals↗
PubMed1999

C-fos expression in the spinal cord of rats exhibiting allodynia following contusive spinal cord injury.

Contusive spinal cord injury (SCI) may result in central neuropathic pain marked by allodynia-like features in the dermatomes close to the level of injury. The aim of this study was to compare the laminar distribution of activated neurons (as determined by c-fos immediate early gene expression) in the spinal cord immediately above the level of a SCI in rats with or without allodynia-like features. Non-noxious mechanical stimulation was applied to half the animals in the dermatomes corresponding to the level of injury prior to perfusion. Stimulation resulted in a significant increase in c-fos labelling in all laminae of the spinal dorsal horn in the segment immediately above the level of injury only in allodynia animals. Animals that had allodynia also demonstrated a significant increase in the level of c-fos labelling in lamina III, IV and V of the dorsal horn without stimulation. Thus, allodynia following SCI is associated with significant increases in basal and evoked c-fos expression ("neuronal activity") in response to non-noxious mechanical stimulation. The data also suggest that allodynia-like behaviour following SCI cannot be accounted for solely by changes occurring at a spinal level.

Animals↗
PubMed1998

Hypotension following acute hypovolaemia depends on the caudal midline medulla.

Acute hypovolaemia evokes abrupt, life-threatening hypotension and bradycardia. Hypotension can be evoked also by excitation of the caudal midline medulla (CMM). This study investigated the possible contribution of the CMM depressor area to hypotension evoked by acute hypovolaemia. Inactivation of the CMM, with either lignocaine or cobalt chloride did not alter resting arterial pressure. However lignocaine injections blocked the fall in arterial pressure, and cobalt chloride injections delayed the onset and significantly attenuated the size of hypovolaemic-evoked hypotension. These findings suggest that the CMM is a key region triggering hypotension after blood loss, and that the brain areas mediating cardiovascular response to challenges such as acute hypovolaemia are not the same areas that regulate resting arterial pressure.

Acute Disease↗
PubMed1998

Vascular head pain selectively activates ventrolateral periaqueductal gray in the cat.

Electrical stimulation of the superior sagittal sinus is an experimental model of migraine which activates neurons within the upper cervical spinal cord. The ventrolateral periaqueductal gray has been proposed as an integrative centre for the autonomic and behavioural responses to deep pain and also receives significant inputs from the upper cervical spinal cord. The noxious-stimulation evoked expression of the immediate-early gene c-fos, was used to determine if sagittal sinus stimulation activates neurons of the ventrolateral periaqueductal gray. The superior sagittal sinus was stimulated in anesthetised cats and Fos-protein was detected in coronal brain sections using standard avidin-biotin immunohistochemistry. A pattern of Fos-positive cells restricted to the caudal ventrolateral periaqueductal gray was revealed suggesting that this region may mediate the pattern of somatic and autonomic responses characteristic of migraine.

Animals↗
PubMed1998

The ventrolateral periaqueductal gray projects to caudal brainstem depressor regions: a functional-anatomical and physiological study.

The reaction of shock, a precipitous, life-threatening fall in arterial pressure and heart rate, is evoked often by the combination of deep pain and blood loss following traumatic injury. A similar "shock-like" pattern of response can be evoked by excitation of the ventrolateral midbrain periaqueductal gray. Further, ventrolateral periaqueductal gray neurons are selectively activated by deep somatic or visceral pain and haemorrhage. The pathways mediating ventrolateral periaqueductal gray evoked hypotension and bradycardia are not known. In this study, the projections from the ventrolateral periaqueductal gray to "cardiovascular" regions in the caudal medulla of the rat were examined. Injections of the anterograde tracer, biotinylated dextran amine at physiologically-defined, ventrolateral periaqueductal gray depressor sites, revealed strong projections to the caudal midline medulla and to the depressor region of the caudal ventrolateral medulla. Injections of excitatory amino acids established that substantial falls in arterial pressure could be evoked from the ventrolateral periaqueductal gray-recipient parts of the caudal midline medulla. Injections of the retrograde tracer, cholera toxin subunit B at physiologically-defined, depressor sites in the caudal midline medulla and the caudal ventrolateral medulla confirmed the existence of substantial projections from the ventrolateral periaqueductal gray. Although previous studies have emphasized the importance of projections from the ventrolateral periaqueductal gray to the pressor region of the rostral ventrolateral medulla, this study has revealed the existence of strong ventrolateral periaqueductal gray projections to depressor regions within the caudal medulla (caudal midline medulla and caudal ventrolateral medulla) which likely contribute to ventrolateral periaqueductal gray-mediated hypotension and bradycardia.

Animals↗
PubMed1998

Swim-stress but not opioid withdrawal increases expression of c-fos immunoreactivity in rat periaqueductal gray neurons which project to the rostral ventromedial medulla.

Expression of c-fos-like immunoreactivity has been used as a marker for neuronal activation and is elevated in the periaqueductal gray following stressful and noxious stimuli, and opioid withdrawal. The present study examined the staining of c-fos-like immunoreactivity following opiate withdrawal or swim-stress (2.5-3 min at 21 degrees C) in periaqueductal gray neurons of the rat which had projections to and through the rostral ventromedial medulla identified by microinjection of the retrograde tracer, Fast Blue, into the nucleus raphe magnus prior to development of morphine dependence. Both naloxone-precipitated withdrawal and swim-stress increased numbers of neurons expressing c-fos-like immunoreactivity in periaqueductal gray. Naloxone-precipitated withdrawal did not increase the number of double-labelled neurons in periaqueductal gray suggesting that neurons excited during opioid withdrawal do not project to the ventromedial medulla. In contrast, swim-stress produced increases in double-labelled neurons in periaqueductal gray suggesting that many periaqueductal gray neurons activated by swim-stress project to the ventromedial medulla. These findings suggest that naloxone-precipitated withdrawal does not activate ventrolateral periaqueductal gray neurons which are involved in descending inhibitory pathways, consistent with behavioural observations that naloxone-precipitated withdrawal is qualitatively opposite to electrical and chemical stimulation of the ventrolateral periaqueductal gray. The results are also consistent with a role of descending projections from periaqueductal gray in stress-induced antinociception.

Animals↗