John P M White

Publications of John P M White

• Xenon fails to inhibit capsaicin-evoked CGRP release by nociceptors in culture.

  Authors: Guy Calcott, John P M White, Istvan Nagy

  Neuroscience letters. 07/2011; 499(2):124-6.

  To investigate whether the xenon-induced inhibition of the transient receptor potential vanilloid type 1 (TRPV1) ion channel in rat dorsal root ganglion (DRG) neurons reduces nociceptive processing,To investigate whether the xenon-induced inhibition of the transient receptor potential vanilloid type 1 (TRPV1) ion channel in rat dorsal root ganglion (DRG) neurons reduces nociceptive processing, we examined the effect of xenon in reducing the release of calcitonin gene-related peptide (CGRP) from those neurons. We found that exposure to xenon failed to effect a reduction of capsaicin-evoked CGRP release from cultured primary sensory neurons when stimulated by capsaicin. This finding suggests that xenon acts on several molecular targets on nociceptive primary sensory neurons, and that xenon's action on one, or more, of those targets serves to offset the inhibitory, pro-analgesic, effect of xenon on TRPV1. It is concluded that xenon may not produce any analgesic effect through peripheral nociceptors.

• Systemic inflammation enhances surgery-induced cognitive dysfunction in mice.

  Authors: António Rei Fidalgo, Mario Cibelli, John P M White, Istvan Nagy, Mervyn Maze, Daqing Ma

  Neuroscience letters. 07/2011; 498(1):63-6.

  The activation of the immune system, by either lipopolysaccharide (LPS) administration or surgical trauma, has been shown to be capable of affecting hippocampal function, causing memory impairment.The activation of the immune system, by either lipopolysaccharide (LPS) administration or surgical trauma, has been shown to be capable of affecting hippocampal function, causing memory impairment. Here, we examined the extent to which LPS-induced infection may aggravate impairment of memory function following orthopaedic surgery. Hippocampal memory function impairment was assessed using fear-conditioning tasks, while IL-1β levels in plasma and hippocampus were measured using ELISA. LPS-induced inflammation disrupted hippocampal memory consolidation as evidenced by reduced contextual freezing time exhibited by infected mice. Likewise, surgery caused hippocampal-dependent memory impairment, which was associated with increased levels of IL-1β both in plasma and hippocampus. However, a sub-pyrogenic dose of LPS alone failed to impair memory function. This dose of LPS, when administered prior to surgery, exacerbated surgery-induced cognitive dysfunction as evidenced by further reduction of contextual freezing time. Also, it caused a concomitant additional increase in the levels of IL-1β in both plasma and hippocampus of those animals. Our data suggest that sub-clinical infection may sensitise the immune system augmenting the severity of post-operative cognitive dysfunction.

• Severe burn injury induces a characteristic activation of extracellular signal-regulated kinase 1/2 in spinal dorsal horn neurons.

  Authors: John P M White, Chin Wing Ko, Antonio Rei Fidalgo, Mario Cibelli, Cleoper C Paule, Peter J Anderson, Celia Cruz, Szabolcs Gomba, Klara Matesz, Gabor Veress, Antonio Avelino, Istvan Nagy

  European journal of pain (London, England). 03/2011; 15(7):683-90.

  We have studied scalding-type burn injury-induced activation of extracellular signal-regulated kinase 1/2 (ERK1/2) in the spinal dorsal horn, which is a recognised marker for spinal nociceptiveWe have studied scalding-type burn injury-induced activation of extracellular signal-regulated kinase 1/2 (ERK1/2) in the spinal dorsal horn, which is a recognised marker for spinal nociceptive processing. At 5min after severe scalding injury to mouse hind-paw, a substantial number of phosphorylated ERK1/2 (pERK1/2) immunopositive neurons were found in the ipsilateral dorsal horn. At 1h post-injury, the number of pERK1/2-labelled neurons remained substantially the same. However, at 3h post-injury, a further increase in the number of labelled neurons was found on the ipsilateral side, while a remarkable increase in the number of labelled neurons on the contralateral side resulted in there being no significant difference between the extent of the labelling on both sides. By 6h post-injury, the number of labelled neurons was reduced on both sides without there being significant difference between the two sides. A similar pattern of severe scalding injury-induced activation of ERK1/2 in spinal dorsal horn neurons over the same time-course was found in mice which lacked the transient receptor potential type 1 receptor (TRPV1) except that the extent to which ERK1/2 was activated in the ipsilateral dorsal horn at 5 min post-injury was significantly greater in wild-type animals when compared to TRPV1 null animals. This difference in activation of ERK1/2 in spinal dorsal horn neurons was abolished within 1h after injury, demonstrating that TRPV1 is not essential for the maintenance of ongoing spinal nociceptive processing in inflammatory pain conditions in mouse resulting from at least certain types of severe burn injury.

• Molecular structure of transient receptor potential vanilloid type 1 ion channel (TRPV1).

  Authors: Laszlo Urban, John P M White, Istvan Nagy

  Current pharmaceutical biotechnology. 11/2010; 12(1):115-21.

  Elaboration of the structure of TRPV1 and its functional relationship with channel activity is a work in progress, with much remaining to be done before the structure-function relationship of TRPV1Elaboration of the structure of TRPV1 and its functional relationship with channel activity is a work in progress, with much remaining to be done before the structure-function relationship of TRPV1 is comprehensively elicited. The result is that the present state of knowledge can reasonably be described as a patch-work of insightful data where major deficits in knowledge remain and where meaningful general conclusions cannot be reliably drawn. This is unfortunate, given that this ion channel has been convincingly implicated in a wide range of physiological functions and pathological conditions. Moreover, the development of therapeutic strategies which target TRPV1 depends on the knowledge of this receptor's structure and its relationship with channel function. Here, we offer a description of the present state of knowledge in relation to this complex subject.

• TRPV1 function in health and disease.

  Authors: John P M White, Laszlo Urban, Istvan Nagy

  Current pharmaceutical biotechnology. 11/2010; 12(1):130-44.

  The transient receptor potential vanilloid type 1 ion channel (TRPV1) was identified as a receptor responsible for mediating the intense burning sensation following exposure to heat greater thanThe transient receptor potential vanilloid type 1 ion channel (TRPV1) was identified as a receptor responsible for mediating the intense burning sensation following exposure to heat greater than approximately 43°C., or capsaicin, the pungent ingredient of hot chilli peppers. More importantly, however, it has been shown that TRPV1 plays a pivotal role in the development of the burning pain sensation associated with inflammation in peripheral tissues. More recently, there has been a virtual avalanche of sightings of TRPV1 on the anatomical landscape, coupled with association of TRPV1 with a wide range of non-pain-related physiological and pathological conditions. Here, we consider the continuously expanding set of functions in both health and disease which TRPV1 is understood to subserve at present. The widespread expression of TRPV1 in the human suggests that, in addition to the development of burning pain associated with acute exposure to heat or capsaicin, and with inflammation, TRPV1 may also be involved in an array of vitally important functions, such as those of the urinary tract, the respiratory and auditory systems. Moreover, TRPV1 could also be involved in the maintenance of body and cell homeostasis, metabolism, regulation of hair growth, and development of cancer. Thus, controlling TRPV1 function may possess the potential of providing exciting opportunities for therapeutic interventions. At the same time, however, the widespread distribution of these ion channels introduces a tremendous complication in developing a drug to serve in one disease context which may have profound implications for normal TRPV1 functioning in other non-pathological contexts.

• Xenon reduces activation of transient receptor potential vanilloid type 1 (TRPV1) in rat dorsal root ganglion cells and in human TRPV1-expressing HEK293 cells.

  Authors: John P M White, Guy Calcott, Agnes Jenes, Mahmuda Hossein, Cleoper C Paule, Peter Santha, John B Davis, Daqing Ma, Andrew S C Rice, Istvan Nagy

  Life sciences. 11/2010; 88(3-4):141-9.

  Xenon provides effective analgesia in several pain states at sub-anaesthetic doses. Our aim was to examine whether xenon may mediate its analgesic effect, in part, through reducing the activity ofXenon provides effective analgesia in several pain states at sub-anaesthetic doses. Our aim was to examine whether xenon may mediate its analgesic effect, in part, through reducing the activity of transient receptor potential vanilloid type 1 (TRPV1), a receptor known to be involved in certain inflammatory pain conditions. We studied the effect of xenon on capsaicin-evoked cobalt uptake in rat cultured primary sensory neurons and in human TRPV1 (hTRPV1)-expressing human embryonic kidney 293 (HEK293) cells. We also examined xenon's effect on the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) in the rat spinal dorsal horn evoked by hind-paw injection of capsaicin. Xenon (75%) reduced the number of primary sensory neurons responding to the TRPV1 agonist, capsaicin (100 nM-1 μM) by ~25% to ~50%. Xenon reduced the number of heterologously-expressed hTRPV1 activated by 300 nM capsaicin by ~50%. Xenon (80%) reduced by ~40% the number of phosphorylated ERK1/2-expressing neurons in rat spinal dorsal horn resulting from hind-paw capsaicin injection. Xenon substantially reduces the activity of TRPV1 in response to noxious stimulation by the specific TRPV1 agonist, capsaicin, suggesting a possible role for xenon as an adjunct analgesic where hTRPV1 is an active contributor to the excitation of primary afferents which initiates the pain sensation.

• Extracellular signal-regulated kinases in pain of peripheral origin.

  Authors: John P M White, Mario Cibelli, Antonio Rei Fidalgo, Istvan Nagy

  European journal of pharmacology. 10/2010; 650(1):8-17.

  Activation of members of the family of enzymes known as extracellular signal-regulated kinases (ERKs) is now known to be involved in the development and/or maintenance of the pain associated withActivation of members of the family of enzymes known as extracellular signal-regulated kinases (ERKs) is now known to be involved in the development and/or maintenance of the pain associated with many inflammatory conditions, such as herniated spinal disc pain, chronic inflammatory articular pain, and the pain associated with bladder inflammation. Moreover, ERKs are implicated in the development of neuropathic pain signs in animals which are subjected to the lumbar 5 spinal nerve ligation model and the chronic constriction injury model of neuropathic pain. The position has now been reached where all scientists working on pain subjects ought to be aware of the importance of ERKs, if only because certain of these enzymes are increasingly employed as experimental markers of nociceptive processing. Here, we introduce the reader, first, to the intracellular context in which these enzymes function. Thereafter, we consider the involvement of ERKs in mediating nociceptive signalling to the brain resulting from noxious stimuli at the periphery which will be interpreted by the brain as pain of peripheral origin.

• Role of transient receptor potential and acid-sensing ion channels in peripheral inflammatory pain.

  Authors: John P M White, Mario Cibelli, Antonio Rei Fidalgo, Cleoper C Paule, Faruq Noormohamed, Laszlo Urban, Mervyn Maze, Istvan Nagy

  Anesthesiology. 03/2010; 112(3):729-41.

  Pain originating in inflammation is the most common pathologic pain condition encountered by the anesthesiologist whether in the context of surgery, its aftermath, or in the practice of painPain originating in inflammation is the most common pathologic pain condition encountered by the anesthesiologist whether in the context of surgery, its aftermath, or in the practice of pain medicine. Inflammatory agents, released as components of the body's response to peripheral tissue damage or disease, are now known to be collectively capable of activating transient receptor potential vanilloid type 1, transient receptor potential vanilloid type 4, transient receptor potential ankyrin type 1, and acid-sensing ion channels, whereas individual agents may activate only certain of these ion channels. These ionotropic receptors serve many physiologic functions-as, indeed, do many of the inflammagens released in the inflammatory process. Here, we introduce the reader to the role of these ionotropic receptors in mediating peripheral pain in response to inflammation.

• Extracellular signal-regulated kinases in pain of peripheral origin

  Authors: John P.M. White, Mario Cibelli, Antonio Rei Fidalgo, Istvan Nagy

  European Journal of Pharmacology.

  Activation of members of the family of enzymes known as extracellular signal-regulated kinases (ERKs) is now known to be involved in the development and/or maintenance of the pain associated withActivation of members of the family of enzymes known as extracellular signal-regulated kinases (ERKs) is now known to be involved in the development and/or maintenance of the pain associated with many inflammatory conditions, such as herniated spinal disc pain, chronic inflammatory articular pain, and the pain associated with bladder inflammation. Moreover, ERKs are implicated in the development of neuropathic pain signs in animals which are subjected to the lumbar 5 spinal nerve ligation model and the chronic constriction injury model of neuropathic pain. The position has now been reached where all scientists working on pain subjects ought to be aware of the importance of ERKs, if only because certain of these enzymes are increasingly employed as experimental markers of nociceptive processing. Here, we introduce the reader, first, to the intracellular context in which these enzymes function. Thereafter, we consider the involvement of ERKs in mediating nociceptive signalling to the brain resulting from noxious stimuli at the periphery which will be interpreted by the brain as pain of peripheral origin.

• Molecular Mechanisms of TRPV1-Mediated Pain

  Authors: Istvan Nagy, Cleoper C. Paule, John P.M. White

  NeuroImmune Biology.

  The transient receptor potential vanilloid type 1 receptor ion channel (TRPV1) (formerly known as the “capsaicin receptor”) plays a crucial role in the excitation of the large subpopulation ofThe transient receptor potential vanilloid type 1 receptor ion channel (TRPV1) (formerly known as the “capsaicin receptor”) plays a crucial role in the excitation of the large subpopulation of nociceptive primary sensory neurons which are sensitive to noxious heat and to a large variety of other pain-inducing stimuli. These ion channels are the important principal mediators of the pain sensations associated with peripheral inflammation which is by far the most important source of pathological pain in humans. Since the cloning of TRPV1, numerous investigations have resulted in the accumulation of substantial amounts of data concerning this ion channel’s molecular, biophysical, and pharmacological properties. Moreover, the mechanisms through which TRPV1 activity may initiate the perception of pain are also beginning to be elucidated. This chapter offers a summary of developments in the rapidly evolving field of TRPV1 research, and considers how TRPV1 activity may contribute to the development of various acute and chronic pain sensations.