A brain-based pain facilitation mechanism contributes to painful diabetic polyneuropathy.

The descending pain modulatory system represents one of the oldest and most fundamentally important neurophysiological mechanisms relevant to pain. Extensive work in animals and humans has shown how a functional imbalance between the facilitatory and inhibitory components is linked to exacerbation and maintenance of persistent pain states. Forward translation of these findings into clinical populations is needed to verify the relevance of this imbalance. Diabetic polyneuropathy is one of the most common causes of chronic neuropathic pain; however, the reason why ∼25–30% of patients with diabetes develop pain is not known. The current study used a multimodal clinical neuroimaging approach to interrogate whether the sensory phenotype of painful diabetic polyneuropathy involves altered function of the ventrolateral periaqueductal grey—a key node of the descending pain modulatory system. We found that ventrolateral periaqueductal grey functional connectivity is altered in patients suffering from painful diabetic polyneuropathy; the magnitude of which is correlated to their spontaneous and allodynic pain as well as the magnitude of the cortical response elicited by an experimental tonic heat paradigm. We posit that ventrolateral periaqueductal grey-mediated descending pain modulatory system dysfunction may reflect a brain-based pain facilitation mechanism contributing to painful diabetic polyneuropathy.Funding for this work was generously provided from the following sources: National Institute for Health Research Oxford Biomedical Research Centre, Medical Research Council of Great Britain and Northern Ireland, the Wellcome Trust (London, UK) and the Innovative Medicines Initiative Joint Undertaking (Brussels, Belgium), under grant agreement no 115007 resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007–2013) and EFPIA companies’ in kind contribution. D.L.B. and A.C.T. are members of the DOLORisk consortium funded by the European Commission Horizon 2020 (ID633491). D.L.B. and A.C.T. are members of the International Diabetic Neuropathy Consortium, the Novo Nordisk Foundation (Ref. NNF14SA0006). D.L.B. is a senior Wellcome clinical scientist (Ref. 202747/Z/16/Z). The project was supported by a strategic award from the Wellcome (Ref. 102645). A.R.S., D.L.B., and I.T. are members of the Wellcome Pain Consortium (Ref. 102645). A.C.T. is an Honorary Research Fellow of the Brain Function Research Group, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa

Medullary control of nociceptive transmission: reciprocal dual communication with the spinal cord

Control of pain perception, essential for organism surviving and recovery from disease, is exerted by higher brain centers integrating nociception with emotional and cognitive information and modulating the brainstem-spinal feedback loops that regulate spinal nociceptive transmission. Development of chronic pain deregulates the forebrain-brainstem-spinal pain control system, which leads to neuroplasticity and disruption of a balanced brain-spinal communication. Targets for impeding pain chronification are being developed using the manipulation of the cross talk between brain and dorsal horn, at both sites of the loop.FCT -Fuel Cell Technologies Program(POCTI/NSE/46399/2002

Central sensitisation and its relevance to chronic pain : FMRI studies in humans

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Similar nociceptive afferents mediate psychophysical and electrophysiological responses to heat stimulation of glabrous and hairy skin in humans

The ability to perceive and withdraw rapidly from noxious environmental stimuli is crucial for survival. When heat stimuli are applied to primate hairy skin, first pain sensation is mediated by type-II A-fibre nociceptors (II-AMHs). In contrast, the reported absence of first pain and II-AMH microneurographical responses when heat stimuli are applied to the hand palm has led to the notion that II-AMHs are lacking in this primate glabrous skin. The aim of this study was to assess the effect of hairy and glabrous skin stimulation on neural transmission of nociceptive inputs elicited by different kinds of thermal heating. We recorded psychophysical and EEG brain responses to radiant (laser-evoked potentials, LEPs) and contact heat stimuli (contact heat-evoked potentials, CHEPs) delivered to the dorsum and the palm of the hand in normal volunteers. Brain responses were analysed at a single-trial level, using an automated approach based on multiple linear regression. Laser stimulation of hairy and glabrous skin at the same energy elicited remarkably similar psychophysical ratings and LEPs. This finding provides strong evidence that first pain to heat does exist in glabrous skin, and suggests that similar nociceptive afferents, with the physiological properties of II-AMHs, mediate first pain to heat stimulation of glabrous and hairy skin in humans. In contrast, when contact heat stimuli were employed, a significantly higher nominal temperature had to be applied to glabrous skin in order to achieve psychophysical ratings similar to those obtained following hairy skin stimulation, and CHEPs following glabrous skin stimulation had significantly longer latencies (N2 wave, +25%; P2 wave, +24%) and smaller amplitudes (N2 wave, −40%; P2 wave, −44%) than CHEPs following hairy skin stimulation. Irrespective of the stimulated territory, CHEPs always had significantly longer latencies (hairy skin N2 wave, +75%; P2 wave, +56%) and smaller amplitudes (hairy skin N2 wave, −42%; P2 wave, −19%) than LEPs. These findings are consistent with the thickness-dependent delay and attenuation of the temperature waveform at nociceptor depth when conductive heating is applied, and suggest that the previously reported lack of first pain and microneurographical II-AMH responses following glabrous skin stimulation could have been the result of a search bias consequent to the use of long-wavelength radiant heating (i.e. CO2 laser) as stimulation procedure

Characterisation and mechanisms of bradykinin-evoked pain in man using iontophoresis

Bradykinin (BK) is an inflammatory mediator that can evoke oedema and vasodilatation, and is a potent algogen signalling via the B1 and B2 G-protein coupled receptors. In naïve skin, BK is effective via constitutively expressed B2 receptors (B2R), while B1 receptors (B1R) are purported to be upregulated by inflammation. The aim of this investigation was to optimise BK delivery to investigate the algesic effects of BK and how these are modulated by inflammation. BK iontophoresis evoked dose- and temperature-dependent pain and neurogenic erythema, as well as thermal and mechanical hyperalgesia (P < 0.001 vs saline control). To differentiate the direct effects of BK from indirect effects mediated by histamine released from mast cells (MCs), skin was pretreated with compound 4880 to degranulate the MCs prior to BK challenge. The early phase of BK-evoked pain was reduced in degranulated skin (P < 0.001), while thermal and mechanical sensitisation, wheal, and flare were still evident. In contrast to BK, the B1R selective agonist des-Arg9-BK failed to induce pain or sensitise naïve skin. However, following skin inflammation induced by ultraviolet B irradiation, this compound produced a robust pain response. We have optimised a versatile experimental model by which BK and its analogues can be administered to human skin. We have found that there is an early phase of BK-induced pain which partly depends on the release of inflammatory mediators by MCs; however, subsequent hyperalgesia is not dependent on MC degranulation. In naïve skin, B2R signaling predominates, however, cutaneous inflammation results in enhanced B1R responses. © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved