PubMed Health⌕ Search

Biomedical subjects

A Dickenson

Publications and source records attributed to A Dickenson.

18 recordsLinked to original sources
PubMed2000

Warm-coding deficits and aberrant inflammatory pain in mice lacking P2X3 receptors.

ATP activates damage-sensing neurons (nociceptors) and can evoke a sensation of pain. The ATP receptor P2X3 is selectively expressed by nociceptors and is one of seven ATP-gated, cation-selective ion channels. Here we demonstrate that ablation of the P2X3 gene results in the loss of rapidly desensitizing ATP-gated cation currents in dorsal root ganglion neurons, and that the responses of nodose ganglion neurons to ATP show altered kinetics and pharmacology resulting from the loss of expression of P2X(2/3) heteromultimers. Null mutants have normal sensorimotor function. Behavioural responses to noxious mechanical and thermal stimuli are also normal, although formalin-induced pain behaviour is reduced. In contrast, deletion of the P2X3 receptor causes enhanced thermal hyperalgesia in chronic inflammation. Notably, although dorsal-horn neuronal responses to mechanical and noxious heat application are normal, P2X3-null mice are unable to code the intensity of non-noxious 'warming' stimuli.

Adenosine Triphosphate↗
PubMed1999

Genetic characterization of wild-type and mutant fur genes of Bordetella avium.

For most, if not all, organisms, iron (Fe) is an essential element. In response to the nutritional requirement for Fe, bacteria evolved complex systems to acquire the element from the environment. The genes encoding these systems are often coordinately regulated in response to the Fe concentration. Recent investigations revealed that Bordetella avium, a respiratory pathogen of birds, expressed a number of Fe-regulated genes (T. D. Connell, A. Dickenson, A. J. Martone, K. T. Militello, M. J. Filiatraut, M. L. Hayman, and J. Pitula, Infect. Immun. 66:3597-3605, 1998). By using manganese selection on an engineered strain of B. avium that carried an Fe-regulated alkaline phosphatase reporter gene, a mutant was obtained that was affected in expression of Fe-regulated genes. To determine if Fe-dependent regulation in B. avium was mediated by a fur-like gene, a fragment of the B. avium chromosome, corresponding to the fur locus of B. pertussis, was cloned by PCR. Sequencing revealed that the fragment from B. avium encoded a polypeptide with 92% identity to the Fur protein of B. pertussis. In vivo experiments showed that the cloned gene complemented H1780, a fur mutant of Escherichia coli. Southern hybridizations and PCRs demonstrated that the manganese mutant had a deletion of 2 to 3 kbp of nucleotide sequence in the region located immediately 5' of the fur open reading frame. A spontaneous PCR-derived mutant of the B. avium fur gene was isolated that encoded a Fur protein in which a histidine was substituted for an arginine at amino acid position 18 (R18H). Genetic analysis showed that the R18H mutant gene when cloned into a low-copy-number vector did not complement the fur mutation in H1780. However, the R18H mutant gene was able to complement the fur mutation when cloned into a high-copy-number vector. The cloned wild-type fur gene will be useful as a genetic tool to identify Fur-regulated genes in the B. avium chromosome.

Amino Acid Sequence↗
PubMed1998

Nociceptin/orphanin FQ. A new opioid, a new analgesic?

Opioids form the major class of strong analgesics. Endogenous opioids and their receptors play important roles in central nervous system function. Thus, the discovery of a new opioid peptide, nociceptin or orphanin FQ, and its receptor, opioid receptor-like 1 (ORL-1) has caused considerable interest since this transmitter system appears to exhibit a number of key differences to the other opioids. Analgesia can be produced at spinal sites but there is compelling evidence that the peptide may also have 'anti-opioid' actions in the brain. Effects on auditory processing, pains from nerve injury coupled with an apparent lack of motivational effects have important implications for novel therapy. This review surveys the recent functional studies on this novel peptide.

Amino Acid Sequence↗
PubMed1998

Iron starvation of Bordetella avium stimulates expression of five outer membrane proteins and regulates a gene involved in acquiring iron from serum.

Iron starvation of Bordetella avium induced expression of five outer membrane proteins with apparent molecular masses of 95, 92, 91.5, 84, and 51 kDa. Iron-responsive outer membrane proteins (FeRPs) of similar sizes were detected in six of six strains of B. avium, suggesting that the five FeRPs are common constituents of the outer membrane of most, if not all, strains of B. avium. Iron-regulated genes of B. avium were targeted for mutagenesis with the transposon TnphoA. Two mutants with iron-responsive alkaline phosphatase activities were isolated from the transposon library. The transposon insertion did not alter the iron-regulated expression of the five FeRPs in mutant Pho-6. The mutant Pho-20 exhibited a loss in expression of the 95-kDa FeRP and the 84-kDa FeRP. Both Pho-6 and Pho-20 were able to use free iron as a nutrient source. However, Pho-20 was severely compromised in its ability to use iron present in turkey serum. The data indicated that the mutation in Pho-20 affected expression of one or more components of an uptake machinery that is involved in acquisition of iron from organic ferricomplexes.

Animals↗
PubMed1997

GABA-receptor control of the amplitude and duration of the neuronal responses to formalin in the rat spinal cord.

The GABAergic inhibitory system in the dorsal horn of the spinal cord has been implicated in the modulation of pain, including the control of nociceptive transmission during inflammation. This electrophysiological study examined the effects of the GABAA and GABAB receptor antagonists, bicuculline and CGP35348, on the magnitude and duration of the formalin response. The responses of spinal nociceptive dorsal horn neurones to subcutaneous injection of formalin into the hindpaw in the anaesthetized rat were recorded. Both phases of the formalin response were monitored, and the antagonists were administered either simultaneously with formalin or 50 min after injection of formalin. Bicuculline (50 microg), the GABAA antagonist, administered simultaneously with formalin significantly increased the magnitude of the overall response, especially the second phase, and also abolished the silent interphase period. In addition, 50 min after injection of formalin, bicuculline increased the duration of the second phase in a dose-dependent manner. CGP35348 (250 microg), the GABAB antagonist, administered 50 min after injection of formalin also increased the duration of the second phase significantly, but had no effect on the magnitude of the response or the silent interphase when administered simultaneously with formalin. These results show that GABAA- and GABAB-receptor-mediated inhibitions are involved in controlling the duration of the second phase of the formalin response, and that GABAA-receptor-mediated inhibition also contributes to the manifestation of the silent interphase period and the magnitude of the second phase. Thus, GABA neurones are critical in determining the level and duration of nociceptive information transmitted through the spinal cord during inflammation.

Journal Article↗
PubMed1995

Spinal opioid systems in inflammation.

Until recently, basic science studies, both behavioural and electrophysiological, have concentrated on the antinociceptive actions of opioids primarily gauged against acute nociceptive responses. However, of more relevance to clinical situations are the actions of opioids in more persistent/prolonged pain states. This review sets out to examine the central actions of opioids against nociception of inflammatory origins. The first section deals with the response of the endogenous opioid system to the development of an inflammatory state and the second examines the ability of exogenous opioids to modulate inflammatory nociception. There are complex changes in the roles of endogenous opioids, in particular dynorphin, at the spinal level after inflammation although the physiological consequences remain unclear. With regard to exogenous opioids, the effectiveness of spinal morphine is rapidly enhanced after inflammation, likely to be due to changes in the interaction between the peptide cholecystokinin and the mu opioid receptor. The ability of inflammatory processes to alter both endogenous opioids and morphine analgesia at the spinal level illustrates the considerable degree of plasticity observed in opioid function.

Analgesia↗
PubMed1994

Pharmacology of chronic pain.

Chronic pain, which is associated with prolonged tissue damage or injuries to the peripheral or central nervous system, results from a number of complex changes in nociceptive pathways. These include alterations of cell phenotype and changes in the expression of proteins such as receptors, transmitters and ion channels, as well as modifications of neural structure, for example, cell loss, nerve regeneration and synaptic reorganizations. The resultant increase in neural excitability can be reduced with receptor-selective drugs that block peripheral or central chemical mediators or that control ectopic activity or cellular phenotype changes. In this article, Andy Dray, Laszlo Urban and Anthony Dickenson focus on some current mechanistic aspects of chronic pain imposed by inflammation and peripheral neuropathy, and review in particular the molecular changes involving the pharmacology of nociceptive pathways since these have important implications for the management of pain.

Analgesics↗
PubMed1991

Systemic capsaicin and olvanil reduce the acute algogenic and the late inflammatory phase following formalin injection into rodent paw.

Systemic capsaicin and an analogue, olvanil (NE-19550, 4-hydroxy-3-methoxyphenyl methyl-9Z-octadecenamide), were tested for antinociceptive activity in a model of persistent pain produced by the subcutaneous injection of formalin into the rodent hind paw. Formalin induced a biphasic nociceptive response in mice and rats which was measured (a) by the time spent licking the injected paw in mice and (b) by making electrophysiological recordings of single nociceptive neurone discharges in L1-L3 of the spinal dorsal horn of halothane-anaesthetised rats. In mice the initial phase of the response was reduced by systemic administration of morphine, capsaicin and olvanil but not by indomethacin. The second, more prolonged, inflammatory phase of the response was reduced by each agent. In rats, similar concentrations of capsaicin and olvanil reduced both the first and second components of the formalin response. These data show that capsaicin and a non-pungent analogue, olvanil, are efficacious antinociceptive agents in a model of prolonged chemical nociception induced by formalin. Their activity compares favourably with that of morphine and appears superior to that of indomethacin.

Animals↗
PubMed1990

Peripheral kappa-opioid modulation of the formalin response: an electrophysiological study in the rat.

The activity of single dorsal horn nociceptive neurones was recorded in the spinal cord of halothane anaesthetized rats. S.c. injection of a 5% formalin solution into the receptive field of these neurones resulted in two peaks of neuronal firing over a period of 60 min. Prior administration of the kappa-opioid receptor agonist U50488H directly into the site of formalin injection caused a dose-dependent decrease in the size of both the first and second peaks of the response which was naloxone reversible. Injection of U50488H into the contralateral paw had no effect on either peak of the formalin response. Injection of the top dose (100 micrograms) of U50488H had no effect on the electrically evoked A beta- or C-fibre responses of the neurone. Neither morphine nor Tyr-D-Ser(Otbu)-Gly-Phe-Leu-Thr (DSTBULET), administered into the receptive field, had any significant effect on either peak of the formalin response. Plasma extravasation in the skin, measured using Evans blue, produced by the formalin injection was not blocked by U50488H. Thus, whilst the spinal responses of this peripheral model of inflammation can be inhibited by peripheral kappa-opioid activation, but not mu- or delta-, plasma extravasation associated with this inflammation is not reduced.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1990

Antinociception produced by capsaicin: spinal or peripheral mechanism?

We have studied the effects of capsaicin, administered at concentrations found to be antinociceptive in behavioural tests, on nociceptive responses evoked both in spinal dorsal horn neurons in vivo and in spinal ventral roots in vitro. In halothane anesthetized rats, C-fibre evoked input produced by transcutaneous electrical stimulation in the peripheral receptive field was recorded from single wide dynamic range neurons located in superficial and deep dorsal horn of the lumbar spinal cord. This input was reduced by systemic administration of capsaicin at an antinociceptive dose (20 mumol/kg s.c.). Intradermal injections of capsaicin localized to the peripheral receptive field produced a transient increase in C-fibre evoked activity followed by a prolonged period of localized insensitivity to C-fibre stimulation. Spinal i.t. administered capsaicin also produced a rapid but reversible attenuation of peripherally evoked C-fibre input. In a neonatal rat spinal cord-tail preparation maintained in vitro, superfusion of the spinal cord with capsaicin (100-500 nM) produced a transient depolarization which was followed by an attenuation of responses to peripheral noxious heat and to spinal administration of substance P. Similar activity was produced by a prolonged superfusion of the spinal cord with substance P (50-200 nM). An HPLC method was used to estimate the concentration of capsaicin in a number of tissues following s.c. administration at an antinociceptive dose. In addition capsaicin concentrations were determined in the spinal cord following an i.t. administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesics↗
PubMed1990

A spinal mechanism of action is involved in the antinociception produced by the capsaicin analogue NE 19550 (olvanil).

We have studied the effect of NE 19550 (olvanil, N-(4-hydroxy-3-methoxyphenyl) methyl-9Z-octadecenamide), a capsaicin analogue with approximately equipotent antinociceptive activity in vivo compared with capsaicin, on nociceptive responses recorded from spinal dorsal horn neurones in vivo and from a spinal ventral root in vitro. In adult rats anaesthetized with halothane, antinociceptive doses of olvanil (20-40 mumol/kg, s.c.) reduced C-fibre responses evoked in wide dynamic range, lumbar dorsal horn neurones, by peripheral transcutaneous electrical stimulation. Intradermal injection of olvanil, localized to a discrete region of the peripheral receptive field, did not activate C-fibres nor change C-fibre evoked activation of dorsal horn neurones. Spinal intrathecal administration of olvanil attenuated C-fibre evoked responses and, at the highest concentration, significantly reduced A beta-fibre evoked activity. In the neonatal rat spinal cord/tail preparation maintained in vitro, superfusion of the cord with olvanil (500 nM-5 microM) did not evoke a depolarization but responses to peripheral noxious stimulation were attenuated. In a similar in vitro preparation of the neonatal rat spinal cord, the release of calcitonin gene-related peptide-like immunoreactivity (CGRP-LI) was measured in spinal cord superfusates. Capsaicin (2-10 microM) evoked a large release of CGRP-LI but olvanil (2-10 microM) produced only a small or undetectable release. Following the administration of each substance, however, the release of CGRP-LI evoked by a depolarizing potassium stimulus was significantly attenuated. These data indicate that C-fibre input to the dorsal horn was attenuated by acute systemic doses of olvanil that were antinociceptive in behavioural tests. This effect was unlikely to be due to impairment of C-fibre function by a peripheral locus of action but was more consistent with an action in the spinal cord in which the reduced release of a neurotransmitter substance from afferent nerve terminals may play a prominent role.

Animals↗
PubMed1988

Long-lasting neuronal activity in rat dorsal horn evoked by impulses in cutaneous C fibres during noxious mechanical stimulation.

The responses of 44 nociceptive neurones in the lumbar dorsal horn evoked by controlled mechanical stimulation of the skin, with or without conduction block in myelinated afferent fibres, were studied in the halothane-anaesthetized rat, in order to evaluate the effects of impulses in cutaneous nociceptive C fibres on dorsal horn neurones. Continuous non-noxious pinch of the skin evoked a short-latency discharge (mean latency 15 ms) in all the 13 class 2 neurones (i.e. neurones responding to both non-noxious and noxious stimulation of the skin) tested. The short-latency discharge was followed by weak prolonged activity in 6 neurones. Following noxious pinch of the skin a prominent late discharge (peak latency 150 ms-2 s) was evoked, which in all but two class 2 neurones outlasted the stimulation period (5-10 s). The discharge evoked by noxious pinch in class 3 neurones (i.e. neurones responding to noxious stimulation only) did not usually outlast the stimulation period. In all but two nociceptive neurones tested (n = 26) the late activity evoked by noxious pinch remained, albeit at a lower frequency in some neurones, during a conduction block in A fibres2,3. Hence this late discharge is probably mainly generated by impulses in nociceptive C fibers. It is concluded that nociceptive C fibres have an important role in sustaining long-lasting activation of class 2 neurones during noxious stimulation of the skin and that long-lasting discharges in these neurones indicates tissue damage to their receptive fields.

Afferent Pathways↗
PubMed1985

Effects of a distant noxious stimulation on A and C fibre-evoked flexion reflexes and neuronal activity in the dorsal horn of the rat.

In the halothane-anaesthetized rat, the responses of 49 neurons in the lumbo-sacral cord and the reflex discharge in the common peroneal nerve following electrical stimulation of the sural nerve were recorded in order to study possible relations between neuronal events and reflex nerve discharges. A distant noxious stimulus (to activate Diffuse Noxious Inhibitory Controls (DNIC) of Le Bars et al.) was used as a conditioning stimulus. Only the responses of neurons receiving an input from both A and C fibres were studied. The neurons were classified as class 1 (low threshold mechanoreceptive input only, n = 2), class 2 (nonnoxious and noxious inputs, n = 34) or class 3 (responding to noxious stimuli only, n = 13). During conditioning stimulation the C fibre evoked discharge was inhibited in 32 out of 34 class 2 neurons. The A fibre-evoked discharge was simultaneously inhibited in 29 of these neurons. The main effect of the distant noxious stimulation on the C fibre evoked neuronal discharge was to decrease the discharge by a constant number of spikes, independent of the level of evoked activity. Only one class 3 neuron was inhibited during conditioning stimulation and none of the class 1 cells were influenced by DNIC. During conditioning stimulation the late and prolonged C fibre evoked reflex nerve discharge (latency 160-200 ms, duration up to several hundred ms) was strongly depressed. Concomitantly, a short-lasting reflex nerve discharge appeared over the interval 115-160 ms. This released reflex nerve discharge (RR) had a constant latency. There was no simultaneous change of the A beta evoked reflex nerve discharge. After the end of the distant noxious stimulation the late C fibre evoked reflex nerve discharge (latency 160-200 ms) recovered. Concomitantly, the RR disappeared. The possibility that the class 2 neurons and the class 3 neurons are intercalated in different reflex pathways is discussed.

Animals↗