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Biomedical subjects

Maria Fitzgerald

Publications and source records attributed to Maria Fitzgerald.

35 records · Page 2Linked to original sources
PubMed2004

Developmental regulation of codeine analgesia in the rat.

BACKGROUND: Codeine analgesia is dependent on metabolism to morphine. Metabolic capability is genetically determined in rats and humans, and individuals can be classified as extensive or poor metabolizers, as determined by the extent of production of morphine. Codeine is often given to infants and children. The aim of this study was to investigate the effects of developmental age on codeine analgesia in rats. METHODS: The effects of codeine were compared with those of morphine using withdrawal reflex responses to mechanical stimuli (with and without inflammation) and to noxious heat in two strains of rats (Sprague-Dawley and Dark Agouti) that have been used to model human metabolic phenotypes because of marked differences in enzyme activity. Effects of the opioids were compared at 3, 10, and 21 days of age and in adult rats. RESULTS: Consistent age-related changes in the efficacy of codeine relative to morphine were noted for both strains of rats. For the extensive metabolizer (Sprague-Dawley) strain, codeine efficacy was substantially lower at 3 days of age (P < 0.001), but there was no difference between the effects of codeine and morphine for 10- and 21-day-old rats and adults (P > 0.05). Poor metabolizers (Dark Agouti strain) also had comparatively low efficacy for codeine compared with morphine in 3-day-old rats and in adults (P < 0.001). In 10- and 21-day-old Dark Agouti rats, there was no difference between either drug (P < 0.05). CONCLUSIONS: Codeine analgesia is developmentally regulated, with low efficacy in the early postnatal period. Effects in the adult rat were not predictive of efficacy in development in either strain, which has important implications for further study and, possibly, for clinical use.

Aging↗
PubMed2003

Spinal dorsal horn cell receptive field size is increased in adult rats following neonatal hindpaw skin injury.

Local tissue damage in newborn rats can lead to changes in skin sensitivity that last into adulthood and this is likely to be due to plasticity of developing peripheral and central sensory connections. This study examines the functional connections of dorsal horn neurons in young and adult rats that have undergone local skin damage at birth. Newborn rat pups were halothane anaesthetised and received either a unilateral subcutaneous plantar injection of 1 % lambda-carrageenan or a unilateral plantar foot injury made by removal of 2 mm x 2 mm of skin. At 3 weeks, (postnatal day (P) 19-23) and 6 weeks (P40-44) in vivo extracellular recordings of single dorsal horn cells with plantar cutaneous receptive fields were made under urethane anaesthesia (2 g kg-1) and responses to mechanical and electrical stimulation of the skin were assessed. Following neonatal carrageenan inflammation, dorsal horn neuron properties and receptive field sizes at 3 weeks were the same as those of controls. In contrast, following neonatal skin injury, dorsal horn cell receptive field sizes were significantly greater than those of controls at 3 weeks (2.5-fold) and at 6 weeks (2.2-fold). Mechanical thresholds, mechanical response magnitudes and evoked responses to single and repeated A and C fibre stimulation remained unaffected. These results show that early skin injury can cause prolonged changes in central sensory connections that persist into adult life, long after the skin has healed. Enlarged dorsal horn neuron receptive field sizes provide a physiological mechanism for the persistent behavioural hypersensitivity that follows neonatal skin injury in rats and for the prolonged sensory changes reported in human infants after early pain and injury.

Animals↗
PubMed2003

Development of nociceptive synaptic inputs to the neonatal rat dorsal horn: glutamate release by capsaicin and menthol.

To study the postnatal development of nociceptive synaptic inputs in the superficial dorsal horn of the neonatal rat spinal cord, we examined the effect of capsaicin and menthol on glutamatergic mEPSCs in postnatal day (P) 0-1, P5-6 and P9-11 slices of spinal cord. Capsaicin (100 nM to 2 microM) increased the mEPSC frequency in a concentration-dependent manner at all ages tested, with a significant enhancement of the effect between P5 and P10. This effect was sensitive to vanilloid receptor (VR) antagonists. The elevation in mEPSC frequency occurred at concentrations of capsaicin (100 nM) that did not alter the distribution of mEPSC amplitudes and was abolished by a dorsal rhizotomy, demonstrating that capsaicin acts via presynaptic VR1 receptors localized on primary afferents. Menthol significantly increased the mEPSC frequency with a similar developmental pattern to capsaicin without consistently affecting mEPSC amplitude. The increase in mEPSC frequency following capsaicin did not depend on transmembrane calcium influx since it persisted in zero [Ca2+]o. The facilitation of spontaneous glutamate release by capsaicin was sufficient to evoke action potentials in neonatal dorsal horn neurons but was accompanied by a block of EPSCs evoked by electrical stimulation of the dorsal root. These results indicate that VR1-expressing nociceptive primary afferents form functional synaptic connections in the superficial dorsal horn from birth and that activation of the VR1 receptor increases spontaneous glutamate release via an undetermined mechanism. In addition, the data suggest that immature primary afferents express functional menthol receptors that are capable of modulating transmitter release. These results have important functional implications for infant pain processing.

Action Potentials↗
PubMed2003

Neonatal inflammation and primary afferent terminal plasticity in the rat dorsal horn.

Abnormal or excessive activity related to pain and injury in early life may alter normal synaptic development and lead to changes in somatosensory processing. The aim of the current study was to define the critical factors that determine long-term plasticity in spinal cord afferent terminals following neonatal inflammation. Hindpaw inflammation was produced in neonatal rat pups with 5 or 25 microl 2% carrageenan, and 5 or 25 microl complete Freund's adjuvant (CFA). All groups displayed a clear inflammatory response that recovered in 2 weeks in all but the 25 microl CFA group, who had persistent chronic inflammation confirmed by histological examination of the paw at 8 weeks. The 25 microl CFA group was also the only group that displayed a significant expansion of the sciatic and saphenous nerve terminal field in lamina II of the dorsal horn at 8 weeks, using wheat-germ agglutinin-horse radish peroxidase transganglionic labelling. This effect was not accompanied by changes in dorsal root ganglion (DRG) cell number, expression of activating transcription factor 3 (ATF3), or alterations in calcitonin gene related peptide (CGRP) or isolectin B4 binding; and was not mimicked by partial nerve damage. No long-term change in mechanical or thermal behavioural sensory thresholds was seen in any group. Lower dose CFA caused an acute, reversible expansion of terminal fields in lamina II in neonatal animals, while CFA did not produce this effect in adults. The duration and effect of neonatal inflammation is therefore dependent on the type and volume of inflammatory agent used. The expansion of afferent terminals in lamina II following neonatal CFA inflammation is maintained into adulthood if the inflammation is also maintained, as seen following 25 microl CFA. This effect is not seen in adult animals, emphasising the plasticity of the nervous system early in development.

Afferent Pathways↗
PubMed2003

De-escalating aggression and violence in the mental health setting.

Aggressive and violent incidents in the health-care setting are increasing phenomena around the world. The evidence from current literature suggests that changes in health-care access, nursing staff shortages and patient acuity are some of the possible causes. De-escalation is a valuable intervention that can be used by nurses to help counter the growing problems of aggression and violence. The de-escalation project, discussed in the present paper, aimed to explore de-escalation as an important therapeutic process and is an event of considerable potential in the management of aggression and violence. While de-escalation is not a new tool, particularly in the mental health-care setting, an educative programme aimed at renewing nurses' knowledge and skills in de-escalation is a timely project. The final de-escalation kit included a large glossy poster, a nursing staff survey, an in-service education session and a literature-based discussion paper. The de-escalation kit can be of considerable benefit to those nurses who are transient within the workplace, such as casual and agency nurses.

Aggression↗
PubMed2002

Wound sensitivity as a measure of analgesic effects following surgery in human neonates and infants.

Postoperative wound sensitivity following abdominal surgery in neonates and infants has been little investigated, and is not well understood. Our aim was to quantify this sensitivity using the abdominal skin reflex (ASR), and to test the hypothesis that the threshold of this reflex would decrease following surgery, and would increase with the administration of analgesia. We measured ASR thresholds in infants under 1 year receiving unilateral abdominal surgery and in a small comparison group of non-surgical infants. The reflex was elicited by applying calibrated von Frey hairs to both sides of the abdomen at the same segmental level. In addition to threshold, the degree of reflex radiation as denoted by hip flexion was measured. The reflex threshold was significantly lowered at the wound site by up to 78% following surgery, and subsequently increased to varying degrees based on the type of analgesia used. The post-surgical drop in threshold was accompanied by an increase in reflex radiation. Thresholds remained below pre-operative values 24 h after surgery on the operated side. In addition, it was observed that infants in whom the indication for surgery was a chronic condition, displayed lower threshold values on the affected side prior to surgery. An objective and quantitative measure has been developed of wound sensitivity and level of analgesia in infants following surgery. The reflex threshold also provides a means of quantifying human central sensory processing, and may be used to detect referred visceral hypersensitivity in this age group.

Abdomen↗
PubMed2002

The postnatal reorganization of primary afferent input and dorsal horn cell receptive fields in the rat spinal cord is an activity-dependent process.

The dorsal horn of the spinal cord in the newborn rat is characterized by large cutaneous mechanoreceptive fields, a predominance of A-fibre synaptic inputs and diffuse primary afferent A-fibre projections, all of which are gradually reduced and refined over the first postnatal weeks. This may be partly responsible for the reduction in cutaneous flexion reflex sensitivity of rats over the postnatal period. Here we show that chronic, local exposure of the dorsal horn of the lumbar spinal cord to the NMDA antagonist MK801 from birth prevents the normal functional and structural reorganization of A-fibre connections. Dorsal horn cells in spinal MK801-treated animals, investigated at eight weeks of age by in vivo electrophysiological recording, had significantly larger cutaneous mechanoreceptive fields and greater A-fibre evoked responses than vehicle controls. C-fibre evoked responses were unaffected. Chronic MK801 also prevented the normal structural reorganization of A-fibre terminals in the spinal cord. The postnatal withdrawal of superficially projecting A-fibre primary afferents to deeper laminae did not occur in treated animals although C-fibre afferent terminals and cell density in the dorsal horn were apparently unaffected. Spinal MK801-treated animals also had significantly reduced behavioural reflex thresholds to mechanical stimulation of the hindpaw compared to naïve and vehicle-treated animals, whereas noxious heat thresholds remained unaffected. The results indicate that the normal postnatal structural and functional development of A-fibre sensory connectivity within the spinal cord is an activity-dependent process requiring NMDA receptor activation.

Afferent Pathways↗
PubMed2002

Age-dependent effects of peripheral inflammation on the electrophysiological properties of neonatal rat dorsal horn neurons.

The aim of this study was to investigate the postnatal development of spinal cord neurophysiological mechanisms of inflammatory pain. The effect of hindpaw inflammation on the properties of neonatal spinal dorsal horn cells was investigated in urethane-anesthetized newborn rats using in vivo single-unit extracellular recordings. Responses to cutaneous mechanical and electrical A and C fiber stimulation were recorded at postnatal day (P) 3, 10, and 21 in pups that had received a unilateral intraplantar carageenan injection (1%, 1 microl/g body wt) 2-5 h earlier and compared with age-matched controls. At all three ages, carageenan inflammation increased A fiber evoked sensitization, spontaneous activity, and the suprathreshold response magnitude of dorsal horn cells. Receptive field size, which normally decreases with postnatal age, was unaffected by inflammation in P3 and P10 pups but significantly increased at P21 so that the size distribution closely resembled that in control P3 pups. Mechanical thresholds of individual dorsal horn neurons were not altered by carageenan inflammation at any age. The results show that some dorsal horn cell properties that are likely to underlie inflammatory hypersensitivity such as increased spontaneous activity and response magnitude are observed from the earliest postnatal age examined (P3). However inflammation induced expansion of mechanical receptive field size is not observed until at least the second postnatal week. These results have implications for the postnatal processing of inflammatory pain.

Age Factors↗
PubMed1999

Epidural opioid analgesia in infant rats I: mechanical and heat responses.

The aim of this study was to investigate the analgesic effects of epidural opioids in neonatal rat pups. The contribution of individual opioid receptor subtypes in the spinal cord to analgesia at different developmental stages was investigated using epidural mu (morphine sulphate), delta (DPDPE) and kappa (U69593) opioid receptor agonists in neonatal rats aged postnatal day (P) 3, 10 and 21. Thresholds for flexion withdrawal reflexes to mechanical stimuli (von Frey hairs) and to noxious heating of the hind paw were low in neonates and increased with postnatal age. The analgesic action of each opioid receptor agonist followed an individual developmental pattern. In mechanical tests, all three opioid agonists were considerably more efficacious analgesics in younger animals and ED50s at P3 were always lower than at P21. In heat tests, the pattern differed. The efficacy of the kappa opioid agonist decreased with postnatal age, morphine efficacy increased over the same period and the effects of the delta agonist remained relatively unchanged. The distribution and concentration of tritiated morphine in the spinal cord following epidural administration did not alter significantly with postnatal age, suggesting that opioid access is not a major determinant of the effects reported here. It is concluded that whereas heat pain is particularly sensitive to spinal kappa opioids in neonates, mechanical sensory thresholds are generally sensitive to all spinal opioids in the newborn. The differing epidural opioid requirements compared to older subjects is likely to be due to developmental changes in spinal cord opioid receptor distribution or pharmacology.

Analgesia, Epidural↗
PubMed1999

Epidural opioid analgesia in infant rats II: responses to carrageenan and capsaicin.

The aim of this study was to investigate the analgesic effects of epidural opioids upon persistent pain sensitivity in neonatal rat pups. Two models of persistent pain were used, subcutaneous injection of carrageenan, and topical application of capsaicin cream, both to the hind paw. The contribution of individual opioid receptor subtypes in the spinal cord to analgesia were tested at different developmental stages using epidural mu (morphine sulphate), delta (DPDPE) and kappa (U69593) opioid receptor agonists in neonatal rats aged P (postnatal day) 3, 10 and 21. Rat pups at all three ages displayed a reduction in mechanical (von Frey hair) threshold following carrageenan-induced inflammation of the hind paw that was evident at 3 h and was still present 5 h after application. This effect was greatest in magnitude at P21. This response was blocked by low doses of all three agonists at all ages, relative effectiveness varying with age. Comparison with potencies in acute tests (Marsh, D., Dickenson, A., Hatch, D. and Fitzgerald, M., Epidural opioid analgesia in infant rats I: mechanical and heat responses, Pain 82 (1999) 23-32) show that opioid potency is significantly greater in the presence of carrageenan inflammation at all ages. Topical capsaicin application to the hind paw produced a significant fall in withdrawal latencies to noxious heat. Generally, epidural opioid agonists did not block this C-fibre induced sensitization except at P3, when morphine and DPDPE did prevent the fall in threshold in a dose dependent manner. The results show that newborn rat pups are capable of displaying both allodynia and hyperalgesia following experimental inflammation that is blocked by epidural mu, delta and kappa opioids. The opioid potency is enhanced compared with antinociception in acute tests. This is not observed following capsaicin hyperalgesia and is therefore not a general consequence of C fibre induced increases in central excitability but relies upon mechanisms special to inflammatory pain.

Analgesia, Epidural↗
PubMed1999

Building blocks of pain: the regulation of key molecules in spinal sensory neurones during development and following peripheral axotomy.

The pathways, synapses and molecules involved in pain processing in the newborn are not only required to trigger repair and recuperation but are also involved in the process of forming a mature nervous system. Sensory neurons in the dorsal root ganglion and dorsal horn express a phenomenal array of molecules which contribute to their structural and functional characteristics and many of these are developmentally regulated both pre- and postnatally. In order to understand nociceptive signalling and pain in the neonate we need a clear picture of that regulation. This review concentrates on the changing expression of selected key molecules, receptors and channels in the embryo, neonate and adult, which both characterise the sensory neuron and contribute to its response to painful stimuli in normal and pathological conditions.

Animals↗
PubMed1994

The cutaneous withdrawal reflex in human neonates: sensitization, receptive fields, and the effects of contralateral stimulation.

The threshold of a cutaneous withdrawal reflex, elicited by calibrated von Frey hairs applied to the foot and leg, has been used to study the development of spinal sensory processing in a group of 50 preterm and full-term infants ranging from 27.5 to 42.5 weeks postconceptional age (PCA). Data sets (108) were collected on initial threshold, the effects of repeated innocuous stimuli, the receptive field of the withdrawal reflex, and the effect of a contralateral stimulus. As reported previously (Fitzgerald et al. 1988, 1989), there was a correlation between PCA and initial threshold. The mean threshold at 29 weeks was 0.237 g (S.E.M. 0.042), whereas the mean threshold at 41 weeks was 0.980 g (S.E.M. 0.134). Repeated stimulation with von Frey hairs led to a significant lowering of threshold or "sensitization" of the reflex in infants of up to 35 weeks PCA. Thereafter, the decrease in threshold was not significant, and habituation was observed. From 27.5 weeks PCA, it was possible to elicit the withdrawal reflex from the whole limb as far up as the top of the thigh and buttock. Below 30 weeks PCA, the thresholds within this receptive field were uniform, but after 30 weeks a gradient of thresholds was observed increasing progressively from the sole of the foot towards the knee. The application of a maintained stimulus to the contralateral limb significantly inhibited withdrawal reflex responses to ipsilateral von Frey hair stimulation, across all age bands. These results illustrate postnatal changes in sensory processing within the human spinal cord.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1991

Functional Connections Formed by Saphenous Nerve Terminal Sprouts in the Dorsal Horn Following Neonatal Sciatic Nerve Section.

The rostrocaudal distribution of saphenous nerve inputs into the lumbar dorsal horn from L2 to L6 has been investigated in urethane anaesthetized rats whose left sciatic nerve was cut and ligated at birth. In normal cord, electrical stimulation of the saphenous nerve evoked dorsal horn spikes in L2 to caudal L4. Few or no spikes were evoked in L5. After neonatal sciatic nerve section, saphenous nerve stimulation evoked spikes throughout segments L2 to L6. Dorsal horn cell receptive fields were also altered following neonatal sciatic nerve section. A somatotopic map of the lumbar enlargement in normal rats was constructed from the receptive fields (RFs) of adjacent dorsal horn cells. Cells with RFs in the saphenous skin region were concentrated in L3 and rostral L4 and very few were found in L5. After neonatal sciatic nerve section, however, a substantial number of cells with low threshold saphenous skin RFs were also found in caudal L4 and throughout L5. These results show that the central saphenous nerve terminal sprouts that grow into the sciatic terminal region following neonatal sciatic nerve section (Fitzgerald, 1985, J. Comp. Neurol., 240, 414-422; Fitzgerald et al., 1990, J. Comp. Neurol., 300, 370-385) form functional connections. This results in dorsal horn cells that are not normally influenced by saphenous nerve inputs developing substantial low threshold RFs in saphenous nerve skin regions.

Journal Article↗
PubMed1989

Cutaneous hypersensitivity following peripheral tissue damage in newborn infants and its reversal with topical anaesthesia.

The flexion reflex threshold has been used as a measure of sensation in a group of premature infants born at 27-32 weeks postmenstrual age. The threshold in an area of local tissue damage created by routine heel lances was half the threshold on the intact heel on the other side. This indicated a hypersensitivity to tissue damage analogous to tenderness or hyperalgesia reported in adults. In a double-blind study, treatment of the damaged area with the topical anaesthetic cream, EMLA, was found to reverse this hypersensitivity or in other words increase the flexion reflex threshold. Treatment with placebo had no effect. The results show that the newborn infant central nervous system is capable of mounting a chronic pain response to local injury which can be reduced by local anaesthetic.

Anesthetics, Local↗
PubMed1980

The stereospecific effect of naloxone on rat dorsal horn neurones; inhibition in superficial laminae and excitation in deeper laminae.

The effect of systemic naloxone on the activity evoked by C-fibre stimulation in dorsal horn neurones of the rat spinal cord has been investigated. Recordings were made in unanaesthetized, decerebrate spinalized rats. Fifteen units were recorded from laminae 4 and 5 of the dorsal horn, 11 of these units were excited by naloxone (0.2--1.0 mg/kg). The onset of this excitation was after 20 sec to 5 min and recovery to control levels occurred within 15--40 min. Of 17 units recorded in substantia gelatinosa of the dorsal horn, 13 were inhibited by the naloxone. The latency of onset of this inhibition was short (2--10 sec) and the effect persisted for 5--10 min. The effects were largely restricted to C-fibre evoked activity although sometimes A delta responses were similarly altered. Neurones stimulated by A beta-fibre threshold, or whose sole afferent input were A beta-fibres, were unaffected by the naloxone. The stereoisomer of naloxone, (+)naloxone which is inactive in opiate receptor binding tests, failed to produce the same changes found with (-)naloxone in 17 units. These results show a differential effect of naloxone on neurones in the dorsal horn which respond to C-fibre input. Units in the substantia gelatinosa are inhibited while units in deeper laminae are excited by naloxone. These effects are likely to be mediated by the blockade of endogenous opioids in the spinal cord.

Animals↗