%0 Journal Article
%~ Pubmed
%A Taylor, Thomas K F
%A Keay, Kevin A
%T A 'ragged' school of anatomy in the 21st century.
%B ANZ Journal of Surgery
%D 2011
%V 81
%N 5
%P 397-8
%@ 1445-2197
%X 
%Z FOR Codes: 1116



%0 Journal Article
%~ Pubmed
%A Mor, David
%A Bembrick, Alison L
%A Austin, Paul J
%A Keay, Kevin A
%T Evidence for cellular injury in the midbrain of rats following chronic constriction injury of the sciatic nerve.
%B Journal of chemical neuroanatomy
%D 2011
%V 41
%N 3
%P 158-69
%@ 1873-6300
%X Complex behavioural disabilities, as well as pain, characterise neuropathic pain conditions for which clinical treatment is sought. In rats, chronic constriction injury (CCI) of the sciatic nerve evokes, allodynia and hyperalgesia as well as three distinct patterns of disability, characterised by changes in social and sleep-wake behaviours: (i) Pain & Disability; (ii) Pain & Transient Disability and (iii) Pain alone. Importantly, the degree of allodynia and hyperalgesia is identical for each of these groups. Social-interactions and sleep-wake behaviours are regulated by neural networks, which converge on the periaqueductal grey (PAG). Rats with Pain & Disability show astrocyte activation restricted to the lateral and ventrolateral PAG. Reactive astrocytes are a hallmark of cell death (apoptosis and necrosis). Quantitative real-time RT-PCR for the mRNAs encoding Bax, Bcl-2, heat shock protein 60 (HSP60), mitogen activated kinase kinase (MEK2) and iNOS was performed on the dorsal midbrains of individual, disability characterised rats, extending our earlier Gene-Chip data, showing a select up-regulation of Bax and MEK2 mRNA, and a down-regulation of HSP60 mRNA, in Pain & Disability rats. The anatomical location of TUNEL and cleaved-caspase-3 immunoreactive profiles in the midbrain was also identified. Rats with Pain & Disability showed: (i) pro-apoptotic ratios of Bax:Bcl-2 mRNAs; (ii) decreased HSP60 mRNA; (iii) increased iNOS and MEK2 mRNAs; (iv) TUNEL-positive profiles in the lateral and ventrolateral PAG; and (v) caspase-3 immunoreactive neurons in the mesencephalic nucleus of the trigeminal nerve. Cell death in these specific midbrain regions may underlie the disabilities characterising this subgroup of nerve-injured rats.
%Z FOR Codes: 110906



%0 Book Section
%A Keay, Kevin
%A Henderson, Luke
%T Physical and Emotional Pain
%B Encyclopedia of Behavioral Neuroscience
%D 2010
%C United States
%I Elsevier Inc.
%V 
%N 
%P 54-63
%@ 9780080453965
%E Koob, George F.
%E Le Moal, Michel
%E Thompson, Richard F.
%X 
%Z FOR Codes: 110906



%0 Journal Article
%~ Pubmed
%A Austin, Paul J
%A Beyer, Konrad
%A Bembrick, Alison L
%A Keay, Kevin A
%T Peripheral nerve injury differentially regulates dopaminergic pathways in the nucleus accumbens of rats with either 'pain alone' or 'pain and disability'.
%B Neuroscience
%D 2010
%V 171
%N 1
%P 329-43
%@ 1873-7544
%X Following unilateral chronic constriction injury (CCI) of the sciatic nerve, histochemical and gene expression changes were examined in the rat nucleus accumbens (NAcc), a region critical to affective-motivational regulation. Rats were categorised as having Pain alone (45%) or Pain and Disability (30%), on the basis of either unaltered or decreased dominance behaviour in the resident-intruder paradigm, respectively. Tyrosine hydroxylase (TH) expression was significantly increased bilaterally, throughout the rostrocaudal extent of the NAcc in Pain alone animals. Increased TH likely reflects increased dopamine levels in the Pain alone group, which may modulate dopamine receptor subtype 2 (D2) receptor expression. Stereological analyses of D2 receptor immunoreactive (D2-IR) cells revealed lateralised changes which correlated significantly with dominance behaviour. In the contralateral NAcc, D2-IR negatively correlated with post-CCI dominance behaviour (i.e. Pain alone animals have decreased D2-IR), whereas ipsilaterally there was a positive correlation between D2-IR and post-CCI dominance behaviour (i.e. Pain and Disability animals have decreased D2-IR). Western blots for D2 protein expression confirmed these correlations. Additionally, D2 mRNA expression within the NAcc showed lateralised and group specific changes. In the ipsilateral NAcc D2 mRNA was increased in Pain alone animals. It is hypothesised that increased D2 mRNA in the ipsilateral NAcc of Pain alone animals may be a protective mechanism, maintaining D2-IR despite increased dopamine, which may otherwise induce receptor desensitisation. D2 mRNA is not altered in the ipsilateral NAcc of Pain and Disability animals, therefore loss of D2-IR is likely, albeit by an alternate mechanism. In summary, unilateral CCI in rats induces specific and lateralised adaptations in the dopaminergic circuitry of the NAcc. These distinct neural adaptations correlate with changes in social behaviour, and likely underlie some of the affective-motivational state changes associated with neuropathic pain in a subset of rats (i.e. Pain and Disability group).
%Z FOR Codes: 110906



%0 Journal Article
%~ Pubmed
%A Shaw, Victoria E
%A Keay, Kevin A
%A Ashkan, Keyoumars
%A Benabid, Alim-Louis
%A Mitrofanis, John
%T Dopaminergic cells in the periaqueductal grey matter of MPTP-treated monkeys and mice; patterns of survival and effect of deep brain stimulation and lesion of the subthalamic nucleus.
%B Parkinsonism & related disorders
%D 2010
%V 16
%N 5
%P 338-44
%@ 1873-5126
%X In this anatomical study, we have examined the number of tyrosine hydroxylase (TH) cells in the periaqueductal grey matter (PAG) of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys and mice; further, we explored whether kainic acid lesion or deep brain stimulation (DBS) of the subthalamic nucleus (STN) in MPTP-treated monkeys has any impact on the number of TH(+) cells in the PAG. For monkeys, there were four groups: Normal, MPTP, STN-lesioned (+MPTP) and STN-DBS (+MPTP). For mice, BALB/c albino mice were divided into three groups, Saline, MPTP_50 (50 mg/kg), MPTP_100 (100 mg/kg). Animals were perfused transcardially with aldehyde fixative 6-12 days after their last MPTP injection. Brains were processed for immunochemistry and the number of cells was estimated using the optical fractionator method. Our results revealed significant reductions (25-30%) in TH(+) cell number in the PAG of MPTP-treated monkeys and mice compared to controls. These reductions were not as substantial as those recorded in the SNc in the same animals (40-60%). Further, in monkeys, there were significantly more TH(+) cells in the PAG of STN-lesioned and STN-DBS groups compared to the MPTP group. In fact, the number of TH(+) cells in the STN alteration cases were similar to the Normal group. In summary, our results indicated that MPTP is toxic to TH(+) cells in the PAG of monkeys and mice and that in monkeys, lesion or DBS of the STN offers neuroprotection against this toxicity.
%Z FOR Codes: 110903



%0 Journal Article
%~ Pubmed
%A Kilburn-Watt, E
%A Banati, R
%A Keay, K A
%T Altered thyroid hormones and behavioural change in a sub-population of rats following chronic constriction injury.
%B Journal of neuroendocrinology
%D 2010
%V 22
%N 8
%P 960-70
%@ 1365-2826
%X Hypothyroidism is associated with a disturbance of behaviour and mood. There are also individuals, not classified as hypothyroid, with low to 'low normal' thyroid hormone levels and normal thyroid-stimulating hormone (TSH) levels who have mood and behavioural changes. As the peripheral thyroid hormones decrease, TSH is expected to increase. However, there are a number of physiological mechanisms known to suppress TSH. In the present study, we report on thyroid hormone regulation in a rat model of neuropathic pain and altered social behaviour that is usually transient, but is persistent in a sub-group of the population. Following ligation of the sciatic nerve, male Sprague-Dawley rats were assessed for social dominance towards an intruder: 20% showed persistently decreased social dominance. Plasma levels of thyroid hormones, TSH and corticosterone were measured before and on days 2, 3, 4, 5 and 6 after injury in 21 rats. The mean plasma thyroxine (T4), free thyroxine (fT4) and triiodothyronine (T3) levels decreased significantly post-injury in rats with persistently changed behaviour compared to rats with unchanged behaviour (P < or = 0.002). There was no significant difference between groups for mean change in free triiodothyronine (fT3) or TSH. There was a correlation between decreased dominance behaviour and decrease in both T4 (r = 0.62, P = 0.009) and fT4 (r = 0.71, P = 0.001), but no correlation with TSH. In a sub-population of rats, decreased thyroid hormones did not result in the expected increased levels of TSH to restore pre-injury levels, nor did they show increased hypothalamic thyrotrophin-releasing hormone mRNA expression, indicating altered hypothalamic-pituitary-thyroid axis regulation. Because T3 availability to the brain is dependent on both circulating T3 and T4, decreased peripheral thyroid hormones may result in changed neural function, as expressed in altered complex behaviours in this sub-population of rats.
%Z FOR Codes: 110306



%0 Journal Article
%~ Pubmed
%A Mor, D
%A Bembrick, A L
%A Austin, P J
%A Wyllie, P M
%A Creber, N J
%A Denyer, G S
%A Keay, K A
%T Anatomically specific patterns of glial activation in the periaqueductal gray of the sub-population of rats showing pain and disability following chronic constriction injury of the sciatic nerve.
%B Neuroscience
%D 2010
%V 166
%N 4
%P 1167-84
%@ 1873-7544
%X Neuropathic pain conditions for which treatment is sought are characterized by complex behavioural disturbances, as well as "pain." Recent studies using chronic constriction injury of the sciatic nerve have shown that rats develop three distinct patterns of disability characterized by changes in social-interactions and sleep-wake cycle behaviours post-injury: (i) Persistent Disability, (ii) Transient Disability and (iii) No Disability. These patterns occur despite all rats showing identical levels of allodynia and hyperalgesia (i.e., pain). In rats, social-interactions and sleep-wake cycle behaviours are regulated in part, by neural networks, which converge on the periaqueductal grey (PAG). We sought therefore to identify neural adaptations in the PAG, 6 days following chronic constriction injury (CCI), the time at which rats in which disabilities persist are first distinguished from those without disabilities (i.e., No Disability and Transient Disability). GeneChips, RT-PCR and Western blotting revealed the select up-regulation in translation and transcription of glial fibrillary acidic protein (GFAP) and Vimentin in rats with Persistent Disability. Significant increases in GFAP immunoreactivity were localized histologically to the lateral and caudal ventrolateral columns of the PAG. This anatomically specific pattern of increased GFAP suggests activation of astrocytes by select neural pathways, which likely include afferents of both spinal and nucleus of the solitary tract (NTS) origin. The PAG columns in which astrocytes are activated play significant roles in modulating both social-interactions and the sleep-wake cycle. It is possible therefore that the persistent disabilities seen in a subgroup of CCI rats are in part a functional consequence of this specific pattern of astrocyte activation.
%Z FOR Codes: 110906



%0 Journal Article
%~ Pubmed
%A McGreevy, Paul D
%A McLean, Andrew N
%A Keay, Kevin A
%A Thomson, Peter C
%T SMART: Sensitivity models for animals in response to training.
%B Veterinary journal (London, England : 1997)
%D 2009
%V 181
%N 1
%P 72-3
%@ 1090-0233
%X Trained responses are said to be under stimulus control when they appear reliably and exclusively on cue. The SMART system is a conceptual, three-dimensional graphic that uses four quadrants to chart a horse's responsiveness to various cues from two reins and the trainer's legs and seat. The current plots have been designed for ridden horses. The models assume that the trainer's cues are bilaterally equivalent, unless the intention is to signal a turn or a lateral movement. The extent to which 'go' signals manifest as straight, forward locomotion reflect the bilateral balance of the horse's reactions to the trainer. The Z-axis shows the probability of a favourable response for the specific strength of stimulus from the trainer relative to competing stimuli from other sources. Where Z is 0 for a particular value of X and Y, the horse shows no desired response to the trainer. The X-axis shows left versus right movement; the Y-axis shows 'stop' versus 'go'.
%Z FOR Codes: 60801



%0 Book Section
%A Keay, Kevin
%A Bandler, Richard
%T Emotional and Behavioral Significance of the Pain Signal and the Role of the Midbrain Periaqueductal Gray (PAG)
%B The Senses: A Comprehensive Reference- Volume 5 Pain
%D 2008
%C United States
%I Elsevier Inc.
%V 
%N 
%P 627?634
%@ 9780123708809
%E Allan, I
%E Basbaum, M
%E Bushnell, Catherine
%X 
%Z FOR Codes: 110906



%0 Journal Article
%~ Pubmed
%A Vagg, D J
%A Bandler, R
%A Keay, K A
%T Hypovolemic shock: Critical involvement of a projection from the ventrolateral periaqueductal gray to the caudal midline medulla.
%B Neuroscience
%D 2008
%V 152
%N 4
%P 1099-109
%@ 0306-4522
%X Previous research has suggested that the ventrolateral column of the periaqueductal gray (vlPAG) plays a crucial role in triggering a decompensatory response (sympathoinhibition, hypotension, bradycardia) to severe blood loss. vlPAG excitation triggers also quiescence, decreased vigilance and decreased reactivity, the behavioral response which usually accompanies hypovolemic shock. The aim of this study was to identify, in unanesthetized rats, the main descending pathway(s) via which vlPAG neurons trigger sympathoinhibition and bradycardia in response to severe blood loss. Firstly, immediate early gene (c-Fos) expression was used to identify vlPAG neurons selectively activated by severe blood loss. Subsequently, the specific medullary projections of these vlPAG neurons were defined by combined c-Fos, retrograde tracing (double-label) experiments. It was found that vlPAG neurons selectively activated by severe hemorrhage project overwhelmingly to the vasodepressor portion of the caudal midline medulla (CMM). Previous studies indicate that this CMM region mediates behaviorally-coupled cardiovascular adjustments and the findings described here fit with the idea that CMM neurons are uniquely recruited by salient challenges, the adaptive responses to which require more than reflexive homeostatic cardiovascular adjustments.
%Z FOR Codes: 110999



%0 Journal Article
%~ Pubmed
%A Hu, Ping
%A Bembrick, Alison L
%A Keay, Kevin A
%A McLachlan, Elspeth M
%T Immune cell involvement in dorsal root ganglia and spinal cord after chronic constriction or transection of the rat sciatic nerve.
%B Brain, behavior, and immunity
%D 2007
%V 21
%N 5
%P 599-616
%@ 0889-1591
%X Chronic constriction injury (CCI) of the sciatic nerve in rodents produces mechanical and thermal hyperalgesia and is a common model of neuropathic pain. Here we compare the inflammatory responses in L4/5 dorsal root ganglia (DRGs) and spinal segments after CCI with those after transection and ligation at the same site. Expression of ATF3 after one week implied that 75% of sensory and 100% of motor neurones had been axotomized after CCI. Macrophage invasion of DRGs and microglial and astrocytic activation in the spinal cord were qualitatively similar but quantitatively distinct between the lesions. The macrophage and glial reactions around neurone somata in DRGs and ventral horn were slightly greater after transection than CCI while, in the dorsal horn, microglial activation (using markers OX-42(for CD11b) and ED1(for CD68)) was greater after CCI. In DRGs, macrophages positive for OX-42(CD11b), CD4, MHC II and ED1(CD68) more frequently formed perineuronal rings beneath the glial sheath of ATF3+ medium to large neurone somata after CCI. There were more invading MHC II+ macrophages lacking OX-42(CD11b)/CD4/ED1(CD68) after transection. MHC I was expressed in DRGs and in spinal sciatic territories to a similar extent after both lesions. CD8+ T-lymphocytes aggregated to a greater extent both in DRGs and the dorsal horn after CCI, but in the ventral horn after transection. This occurred mainly by migration, additional T-cells being recruited only after CCI. Some of these were probably CD4+. It appears that inflammation of the peripheral nerve trunk after CCI triggers an adaptive immune response not seen after axotomy.



%0 Journal Article
%~ Pubmed
%A Allbutt, Haydn N
%A Siddall, Phillip J
%A Keay, Kevin A
%T Contusive spinal cord injury evokes localized changes in NADPH-d activity but extensive changes in Fos-like immunoreactivity in the rat.
%B Journal of anatomy
%D 2007
%V 211
%N 3
%P 352-70
%@ 0021-8782
%X The histological detection of nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d), a marker for nitric oxide-producing cells, was used to evaluate ongoing changes in the neural biochemistry of the rat spinal cord 1 week following contusive spinal cord injury (SCI). In addition, the immunohistochemical detection of the immediate-early gene c-fos was used to identify basal patterns of neural activity at this time. The numbers and laminar locations of NADPH-d- and c-fos-positive cells were examined in spinal segments adjacent to the site of injury (T12-S3) as well as those distant from the injury (C3-C5) in both SCI and un-injured rats. Our data show that contusive SCI results in a significant reduction in NADPH-d labelling in the superficial dorsal horn, and a significant increase in NADPH-d expression in small bipolar neurons and large motoneurons in the ventral horn at the site of the injury. In spinal segments distant to the injury site (C3-C5), NADPH-d activity did not differ from that of uninjured controls. Furthermore, significant reductions in the levels of c-fos expression were observed in SCI rats, in spinal segments both at and distant to the site of injury for all spinal laminae. The only exception was a dramatic increase observed in the sacral parasympathetic nucleus. These data suggest that increased NADPH-d expression is related to conditions specific to the site of injury, whereas the changes in c-fos expression probably indicate more global changes in neuronal activity following SCI.
%Z FOR Codes: 110903



%0 Journal Article
%~ Pubmed
%A Hacker, J
%A Pedersen, N P
%A Chieng, B C H
%A Keay, K A
%A Christie, M J
%T Enhanced Fos expression in glutamic acid decarboxylase immunoreactive neurons of the mouse periaqueductal grey during opioid withdrawal.
%B Neuroscience
%D 2006
%V 137
%N 4
%P 1389-96
%@ 0306-4522
%X 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.
%Z FOR Codes: 110903



%0 Journal Article
%~ Pubmed
%A Brown, Heidi J
%A Henderson, Luke A
%A Keay, Kevin A
%T Hypotensive but not normotensive haemorrhage increases tryptophan hydroxylase-2 mRNA in caudal midline medulla.
%B Neuroscience Letters
%D 2006
%V 398
%N 3
%P 314-8
%@ 0304-3940
%X Severe blood loss triggers shock, a precipitous hypotension and bradycardia. The integrity of (i) neurons in the vasodepressor region of the caudal midline medulla and (ii) central 5-HT neurotransmission are critical for the expression of haemorrhagic shock. This study investigated whether progressive blood loss triggers altered synthesis of 5-HT in the vasodepressor region of the caudal midline medulla by measuring changes in relative expression levels of tryptophan hydroxylase 2 (TpH 2) mRNA, the rate-limiting enzyme in the synthesis of neuronal 5-HT. Hypotensive but not normotensive haemorrhage triggered a significant increase in TpH 2 mRNA in the vasodepressor region of the caudal midline medulla, identifying an important role for 5-HT-containing caudal midline medullary neurons in haemorrhagic shock.
%Z FOR Codes: 110906



%0 Journal Article
%~ Pubmed
%A Walker, Suellen M
%A Howard, Richard F
%A Keay, Kevin A
%A Fitzgerald, Maria
%T Developmental age influences the effect of epidural dexmedetomidine on inflammatory hyperalgesia in rat pups.
%B Anesthesiology
%D 2005
%V 102
%N 6
%P 1226-34
%@ 0003-3022
%X BACKGROUND: Epidural alpha2-adrenergic agonists produce analgesic effects in children and adults, but efficacy and safety have not been established in neonates and infants. The aim of this study was to determine the effect of epidural dexmedetomidine on sensory processing, reversal of inflammatory hyperalgesia, and sedation during early development in rats. METHODS: In rat pups aged 3, 10, and 21 postnatal days, mechanical withdrawal thresholds of the hind limbs were measured at baseline and after unilateral inflammation due to carrageenan. The effect of epidural dexmedetomidine on withdrawal thresholds was measured for 90 min after injection, and dose-response curves were constructed for each age group. The duration of the righting reflex was measured to assess sedation. The effects of epidural and systemic administration of dexmedetomidine were compared. RESULTS: At all ages, carrageenan-induced hyperalgesia was reversed by doses of epidural dexmedetomidine that did not affect the threshold of the contralateral paw or prolong the righting reflex. Higher doses of epidural dexmedetomidine affected baseline nociception in the contralateral paw and produced sedation but had no effect when given systemically. Reversal of hyperalgesia and sedation were produced by lower doses of epidural dexmedetomidine in the youngest pups. CONCLUSIONS: Spinally mediated selective reversal of inflammatory hyperalgesia by epidural dexmedetomidine can be achieved at all ages; relatively lower doses are effective in early life, but the therapeutic window is narrow. These data have implications for the use and dosing of epidural alpha2 agonists in neonates and infants.
%Z FOR Codes: 110906



%0 Journal Article
%~ Pubmed
%A Keay, Kevin A
%A Monassi, Claudia R
%A Levison, Dane B
%A Bandler, Richard
%T Peripheral nerve injury evokes disabilities and sensory dysfunction in a subpopulation of rats: a closer model to human chronic neuropathic pain?
%B Neuroscience Letters
%D 2004
%V 361
%N 1-3
%P 188-91
%@ 0304-3940
%X Chronic pain conditions for which treatment is sought are characterized usually by complex behavioural disturbances as well as pain. We review here evidence that although chronic constriction injury (CCI) of the sciatic nerve evokes allodynia and hyperalgesia in all rats, persistent social behavioural and sleep disruption occurs only in a subpopulation of animals. The finding that the 'degree of pain', as defined by allodynia and hyperalgesia, is the same in all animals suggests that the complex behavioural disabilities are independent of the level of sensory dysfunction. An absence of correlation between disability and sensory dysfunction is characteristic also of human neuropathic pain. These findings indicate that: (i). in a subpopulation of rats sciatic injury evokes disabilities characteristic of human neuropathic pain conditions; and (ii). testing for sensory dysfunction alone cannot detect this subpopulation.



%0 Journal Article
%~ Pubmed
%A Heslop, David J
%A Bandler, Richard
%A Keay, Kevin A
%T Haemorrhage-evoked decompensation and recompensation mediated by distinct projections from rostral and caudal midline medulla in the rat.
%B The European journal of neuroscience
%D 2004
%V 20
%N 8
%P 2096-110
%@ 0953-816X
%X The haemodynamic response to blood loss consists of three phases: (i) an initial compensatory phase during which resting arterial pressure is maintained; (ii) a decompensatory phase characterized by a sudden, life-threatening hypotension and bradycardia; and (iii) if blood loss ceases, a recompensatory phase during which arterial pressure returns to normal. Previous research indicates that topographically distinct, rostral and caudal parts of the caudal midline medulla (CMM) contain neurons that differentially regulate the timing and magnitude of each of the three phases. Specifically, decompensation depends critically on the integrity of the rostral CMM; whereas compensation and recompensation depend upon the integrity of the caudal CMM. This study aimed to determine, using retrograde and anterograde tracing techniques, if the rostral and caudal CMM gave rise to different sets of projections to the major cardiovascular region of the ventrolateral medulla (VLM) and spinal cord. It was found that rostral and caudal CMM each have projections of varying density to the region containing bulbospinal (presympathetic) motor neurons in the rostral VLM and preganglionic sympathetic motor neurons in the intermediolateral cell column of the spinal cord. Via these projections vasomotor tone and hence arterial pressure can be regulated. More strikingly: (i) consistent with a role in mediating bradycardia during decompensation, the rostral CMM projects uniquely to VLM regions containing vagal cardiac motor neurons; and (ii) consistent with its role in mediating recompensation, the caudal CMM projects uniquely onto tyrosine hydroxylase-containing, caudal VLM (A1) neurons whose activity mediates vasopressin release, on which recompensation depends.



%0 Journal Article
%~ Pubmed
%A Potas, Jason R
%A Keay, Kevin A
%A Henderson, Luke A
%A Bandler, Richard
%T Somatic and visceral afferents to the 'vasodepressor region' of the caudal midline medulla in the rat.
%B The European journal of neuroscience
%D 2003
%V 17
%N 6
%P 1135-49
%@ 0953-816X
%X Previous research has found that the integrity of a restricted region of the caudal midline medulla (including caudal portions of nucleus raph? obscurus and nucleus raph? pallidus) was critical for vasodepression (hypotension, bradycardia, decreased cardiac contractility) evoked either by haemorrhage or deep pain. In this anatomical tracing study we found that the vasodepressor part of the caudal midline medulla (CMM) receives inputs arising from spinal cord, spinal trigeminal nucleus (SpV) and nucleus of the solitary tract (NTS). Specifically: (i) a spinal-CMM projection arises from neurons of the deep dorsal horn, medial ventral horn and lamina X at all spinal segmental levels, with approximately 60% of the projection originating from the upper cervical spinal cord (C1-C4); (ii) a SpV-CMM projection arises primarily from neurons at the transition between subnucleus caudalis and subnucleus interpolaris; (iii) a NTS-CMM projection arises primarily from neurons in ventrolateral and medial subnuclei. In combination, the specific spinal, SpV and NTS regions which project to the CMM receive the complete range of somatic and visceral afferents known to trigger vasodepression. The role(s) of each specific projection is discussed.
%Z FOR Codes: 110999



%0 Journal Article
%~ Pubmed
%A Troy, B P
%A Heslop, D J
%A Bandler, R
%A Keay, K A
%T Haemodynamic response to haemorrhage: distinct contributions of midbrain and forebrain structures.
%B Autonomic neuroscience : basic & clinical
%D 2003
%V 108
%N 1-2
%P 1-11
%@ 1566-0702
%X 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.
%Z FOR Codes: 110999



%0 Journal Article
%~ Pubmed
%A Monassi, Claudia R
%A Bandler, Richard
%A Keay, Kevin A
%T A subpopulation of rats show social and sleep-waking changes typical of chronic neuropathic pain following peripheral nerve injury.
%B The European journal of neuroscience
%D 2003
%V 17
%N 9
%P 1907-20
%@ 0953-816X
%X Neuropathic conditions for which treatment is sought, the so-called chronic pain syndrome, are characterized usually by complex behavioural disturbances as well as pain. In this study we evaluated whether social behavioural and sleep disruptions occurred after nerve injury. Before and after chronic constriction of the sciatic nerve, resident-intruder and sleep-wake cycles, as well as mechanical and thermal allodynia/hyperalgesia, were quantified. Sciatic nerve injury in all animals reduced withdrawal thresholds to tactile and thermal (cold) stimuli. Resident-intruder and sleep-waking behaviours were altered in some but not all animals. One group (30%, 'persistent change') had enduring reductions in dominant behaviour to an intruder and decreased slow-wave sleep and increased wakefulness during both light and dark cycles. Another group (25%, 'recovery') had a transient reduction in dominant behaviours and decreased slow-wave sleep and increased wakefulness during only the light cycle. In a third group (45%, 'no effect') resident-intruder and sleep-waking behaviours remained normal. Our finding that the degree of 'pain' as inferred from the allodynia/hyperalgesia was identical in all animals suggests that the alterations to resident-intruder and sleep-wake cycles were independent of the level of sensory disturbance. An absence of correlation between intensity of sensory disturbances and measures of disability (loss of sleep, familial/social problems) is also characteristic of human neuropathic pain. These data indicate that: (i) in a subpopulation of animals sciatic injury results in two of the major complex behavioural changes which are characteristic of neuropathic pain in humans; (ii) testing only for allodynia and hyperalgesia is not sufficient to detect this subpopulation.
%Z FOR Codes: 110999



%0 Journal Article
%~ Pubmed
%A Keay, K A
%A Clement, C I
%A Matar, W M
%A Heslop, D J
%A Henderson, L A
%A Bandler, R
%T Noxious activation of spinal or vagal afferents evokes distinct patterns of fos-like immunoreactivity in the ventrolateral periaqueductal gray of unanaesthetised rats.
%B Brain Research
%D 2002
%V 948
%N 1-2
%P 122-30
%@ 0006-8993
%X 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.
%Z FOR Codes: 110999



%0 Journal Article
%A Keay, KA
%A Bandler, RJ
%T Physiological Society Symposium Nociceptors as Homeostatic Afferents: Central Processing Distict central representations of inescapable & escapable pain: observations & speculation
%B Experimental Physiology
%D 2002
%C 40 West 20Th St, New York, Ny, 10011-4221
%I Cambridge Univ Press
%V 87.2
%N 
%P 275-279
%@ 0958-0670
%X 



%0 Journal Article
%~ Pubmed
%A Keay, Kevin A
%A Bandler, Richard
%T Distinct central representations of inescapable and escapable pain: observations and speculation.
%B Experimental physiology
%D 2002
%V 87
%N 2
%P 275-9
%@ 0958-0670
%X It is well established clinically that the affective response to pain of deep origin (muscles, joints and viscera) is distinct from that evoked by cutaneous pain. Cutaneous pain triggers a fight-flight reaction (active emotional coping), whereas deep pain evokes a reaction of quiescence, decreased vigilance and vasodepression (passive emotional coping). These observations led to suggestions of distinct central representations for deep versus cutaneous pain. Indeed, studies using immediate early gene (c-fos) expression revealed selective activation of ventrolateral versus lateral columns of the midbrain periaqueductal grey region (PAG) by persistent pain of deep origin versus intermittent cutaneous pain. Ventrolateral versus lateral PAG activation had been found earlier to evoke passive versus active emotional coping. However, not all cutaneous pain triggers active coping. Persistent cutaneous pain (e.g. burns) instead, usually evokes passive coping. This raised the question of whether the behavioural significance of pain (i.e. its escapability versus inescapability), rather than its tissue origin, is represented in supraspinal regions such as the PAG. Subsequent study revealed that a persistent (inescapable) noxious cutaneous manipulation (clip of the neck) evoked both selective ventrolateral PAG Fos expression and passive emotional coping. Such data suggest that pain representation in the PAG reflects a quality akin to behavioural significance, rather than tissue origin. In contrast, in the spinal cord predominantly superficial dorsal horn Fos expression was seen after either persistent or intermittent noxious cutaneous stimuli, leaving the question of the pathway(s) via which persistent (inescapable) cutaneous pain activates the vlPAG unanswered. One experimental approach to this question is suggested.
%Z FOR Codes: 110906



%0 Journal Article
%~ Pubmed
%A Henderson, Luke A
%A Keay, Kevin A
%A Bandler, Richard
%T Delta- and kappa-opioid receptors in the caudal midline medulla mediate haemorrhage-evoked hypotension.
%B NeuroReport
%D 2002
%V 13
%N 5
%P 729-33
%@ 0959-4965
%X In mammals blood loss can trigger, shock, an abrupt, life-threatening hypotension and bradycardia. In the halothane-anaesthetised rat this response is blocked by inactivation of a discrete, vasodepressor area in the caudal midline medulla (CMM). Haemorrhagic shock is blocked also by systemic or ventricular injections of the opioid antagonist, naloxone. This study investigated, in the halothane anaesthetised rat, the contribution of delta-, kappa- and mu-opioid receptors in the CMM vasodepressor region to haemorrhage-evoked shock (i.e. hypotension and bradycardia) and its recovery. It was found that microinjections into the CMM of the delta-opioid receptor antagonist, naltrindole delayed and attenuated the hypotension and bradycardia evoked by haemorrhage, but did not promote recompensation. In contrast, CMM microinjections of the kappa-opioid receptor antagonist, nor-binaltorphamine, although it did not alter haemorrhage-evoked hypotension and bradycardia, did lead to a rapid restoration of AP, but not HR. CMM microinjections of the mu-opioid receptor antagonist, CTAP had no effect on haemorrhage-evoked shock or recompensation. These data indicate that delta- and kappa- (but not mu-) opioid receptor-mediated events within the CMM contribute to the hypotension and bradycardia evoked by haemorrhage and the effectiveness of naloxone in reversing shock.
%Z FOR Codes: 110999



%0 Journal Article
%~ Pubmed
%A Heslop, D J
%A Keay, K A
%A Bandler, R
%T Haemorrhage-evoked compensation and decompensation are mediated by distinct caudal midline medullary regions in the urethane-anaesthetised rat.
%B Neuroscience
%D 2002
%V 113
%N 3
%P 555-67
%@ 0306-4522
%X 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.
%Z FOR Codes: 110999



%0 Journal Article
%~ Pubmed
%A Floyd, N S
%A Price, J L
%A Ferry, A T
%A Keay, K A
%A Bandler, R
%T Orbitomedial prefrontal cortical projections to hypothalamus in the rat.
%B The Journal of Comparative Neurology
%D 2001
%V 432
%N 3
%P 307-28
%@ 0021-9967
%X 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.
%Z FOR Codes: 110999



%0 Journal Article
%~ Pubmed
%A Keay, K A
%A Bandler, R
%T Parallel circuits mediating distinct emotional coping reactions to different types of stress.
%B Neuroscience and biobehavioral reviews
%D 2001
%V 25
%N 7-8
%P 669-78
%@ 0149-7634
%X 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.
%Z FOR Codes: 110999



%0 Journal Article
%A Clement, C
%A Keay, KA
%A Podzebenko, K
%A Gordon, B
%A Bandler, RJ
%T Spinal sources of noxious visceral and noxious deep somatic afferent drive onto the ventrolateral periaqueductal gray of the rat
%B The Journal of Comparative Neurology
%D 2000
%C 
%I Wiley-Liss, Inc
%V 425 (3)
%N 
%P 323-344
%@ 1021-9967
%X 



%0 Journal Article
%A Bandler, RJ
%A Price, JL
%A Keay, KA
%T Brain mediation of active and passive emotional coping
%B Progress in Brain Research
%D 2000
%C 
%I Elsevier Science BV
%V 122
%N 
%P 333-349
%@ 0079-6123
%X 



%0 Journal Article
%A Henderson, LA
%A Keay, KA
%A Bandler, RJ
%T Caudal Midline Medulla Mediates Behaviourally-coupled but not Baroreceptor-mediated vasodepression
%B Neuroscience
%D 2000
%C 
%I Pergamon-Elsevier Science Ltd
%V 98 (4)
%N 
%P 779-792
%@ 0306-4522
%X 



%0 Journal Article
%A Bandler, RJ
%A Keay, KA
%A Floyd, N
%A Price, J
%T Central circuits mediating patterned autonomic activity during active vs. passive emotional coping
%B Brain Research Bulletin
%D 2000
%C 
%I Pergamon-Elsevier Science Ltd
%V 53 (1)
%N 
%P 95-104
%@ 0361-9230
%X 



%0 Journal Article
%A Floyd, N
%A Price, JL
%A Ferry, AT
%A Keay, KA
%A Bandler, RJ
%T Orbitomedial prefrontal cortical projections to distinct longitudinal columns of the periaqueductal gray in the rat
%B The Journal of Comparative Neurology
%D 2000
%C 
%I Wiley-Liss, Inc
%V 422 (2)
%N 
%P 556-578
%@ 0021-9967
%X 



%0 Journal Article
%A Keay, KA
%A Li, QF
%A Bandler, RJ
%T Muscle pain activates a direct projection from vetrolateral periaqueductal gray to rostral ventrolateral medulla in rats
%B Neuroscience Letters
%D 2000
%C 
%I Elsevier Sci Ireland Ltd
%V 290 (3)
%N 
%P 157-160
%@ 0304-3940
%X 



%0 Book Section
%A Keay, KA
%A Clement, C
%A Bandler, RJ
%T The Neuroanatomy of Cardiac Nociceptive Pathways: Differential Representations of
%B The Nervous System & the Heart
%D 2000
%C 
%I Humana Press
%V 
%N 
%P 303-342
%@ 0-89603-693-6
%X