Pain, purines and Geoff

The story of purinergic neurotransmission and regulation is intimately linked to studies of the somatosensory system. Burnstock's contributions to the discovery of ATP as a primary afferent neurotransmitter, as well as a signal of peripheral tissue damage that depolarised sensory neurons initiated a new period of pain research. The neuro-immune interactions that occur after tissue damage and are important for pain have now also been found to involve purinergic signalling, and adenosine has been demonstrated to have significant analgesic effects. In the pain field as in so many other areas of neuroscience and physiology, Burnstock's contributions have been critical to the expansion of our knowledge about the significance of purines. His mechanistic insights have profound significance for understanding the pain system and further underscore his stature as a pioneer and force for progress in biomedicine

FM1-43 is a permeant blocker of mechanosensitive ion channels in sensory neurons and inhibits behavioural responses to mechanical stimuli

The molecular identity and pharmacological properties of mechanically gated ion channels in sensory neurons are poorly understood. We show that FM1-43, a styryl dye used to fluorescently label cell membranes, permeates mechanosensitive ion channels in cultured dorsal root ganglion neurons, resulting in blockade of three previously defined subtypes of mechanically activated currents. Blockade and dye uptake is voltage dependent and regulated by external Ca(2+). The structurally related larger dye FM3-25 inhibited mechanically activated currents to a lesser degree and did not permeate the channels. In vivo, FMI-43 decreases pain sensitivity in the Randall-Selitto test and increases the withdrawal threshold from von Frey hairs, together suggesting that the channels expressed at the cell body in culture mediate mechanosensation in the intact animal. These data give further insight into the mechanosensitive ion channels expressed by somatosensory neurons and suggest FM dyes are an interesting tool for studying them

Pregabalin silences oxaliplatin-activated sensory neurons to relieve cold allodynia

Oxaliplatin is a platinum-based chemotherapeutic agent that causes cold and mechanical allodynia in up to 90% of patients. Silent Nav1.8-positive nociceptive cold sensors have been shown to be unmasked by oxaliplatin, and this event has been causally linked to the development of cold allodynia. We examined the effects of pregabalin on oxaliplatin-evoked unmasking of cold sensitive neurons using mice expressing GCaMP-3 in all sensory neurons. Intravenous injection of pregabalin significantly ameliorates cold allodynia, while decreasing the number of cold sensitive neurons by altering their excitability and temperature thresholds. The silenced neurons are predominantly medium/large mechano-cold sensitive neurons, corresponding to the 'silent' cold sensors activated during neuropathy. Deletion of α2δ1 subunits abolished the effects of pregabalin on both cold allodynia and the silencing of sensory neurons. Thus, these results define a novel, peripheral inhibitory effect of pregabalin on the excitability of 'silent' cold-sensing neurons in a model of oxaliplatin-dependent cold allodynia.Significance StatementPregabalin is an analgesic drug in the clinic, that is supposed to act by blocking neurotransmitter release. Here we show that silent nociceptors that are activated by chemotherapeutic insults like oxaliplatin are silenced by pregabalin, which blocks the associated pain. This mode of action suggests that peripheral acting pregabalin-like drugs could be very useful for pain during chemotherapy, as they would have no CNS side effects - a problem for many patients with pregabalin. This novel effect of pregabalin is mediated by its interaction with the α2δ1 calcium channel subunit, but how this works is not yet understood

Na(v )1.8-null mice show stimulus-dependent deficits in spinal neuronal activity

BACKGROUND: The voltage gated sodium channel Na(v )1.8 has a highly restricted expression pattern to predominantly nociceptive peripheral sensory neurones. Behaviourally Na(v )1.8-null mice show an increased acute pain threshold to noxious mechanical pressure and also deficits in inflammatory and visceral, but not neuropathic pain. Here we have made in vivo electrophysiology recordings of dorsal horn neurones in intact anaesthetised Na(v )1.8-null mice, in response to a wide range of stimuli to further the understanding of the functional roles of Na(v )1.8 in pain transmission from the periphery to the spinal cord. RESULTS: Na(v )1.8-null mice showed marked deficits in the coding by dorsal horn neurones to mechanical, but not thermal, -evoked responses over the non-noxious and noxious range compared to littermate controls. Additionally, responses evoked to other stimulus modalities were also significantly reduced in Na(v )1.8-null mice where the reduction observed to pinch > brush. The occurrence of ongoing spontaneous neuronal activity was significantly less in mice lacking Na(v )1.8 compared to control. No difference was observed between groups in the evoked activity to electrical activity of the peripheral receptive field. CONCLUSION: This study demonstrates that deletion of the sodium channel Na(v )1.8 results in stimulus-dependent deficits in the dorsal horn neuronal coding to mechanical, but not thermal stimuli applied to the neuronal peripheral receptive field. This implies that Na(v )1.8 is either responsible for, or associated with proteins involved in mechanosensation

Using the UM dynamical cores to reproduce idealised 3D flows

We demonstrate that both the current (New Dynamics), and next generation (ENDGame) dynamical cores of the UK Met Office global circulation model, the UM, reproduce consistently, the long-term, large-scale flows found in several published idealised tests. The cases presented are the Held-Suarez test, a simplified model of Earth (including a stratosphere), and a hypothetical tidally locked Earth. Furthermore, we show that using simplifications to the dynamical equations, which are expected to be justified for the physical domains and flow regimes we have studied, and which are supported by the ENDGame dynamical core, also produces matching long-term, large-scale flows. Finally, we present evidence for differences in the detail of the planetary flows and circulations resulting from improvements in the ENDGame formulation over New Dynamics.Comment: 34 Pages, 23 Figures. Accepted for publication in Geoscientific Model Development (pre-proof version

The “pain matrix” in pain-free individuals

Human functional imaging provides a correlative picture of brain activity during pain. A particular set of central nervous system structures (eg, the anterior cingulate cortex, thalamus, and insula) consistently respond to transient nociceptive stimuli causing pain. Activation of this so-called pain matrix or pain signature has been related to perceived pain intensity, both within and between individuals,1,2 and is now considered a candidate biomarker for pain in medicolegal settings and a tool for drug discovery. The pain-specific interpretation of such functional magnetic resonance imaging (fMRI) responses, although logically flawed,3,4 remains pervasive. For example, a 2015 review states that “the most likely interpretation of activity in the pain matrix seems to be pain.”4 Demonstrating the nonspecificity of the pain matrix requires ruling out the presence of pain when highly salient sensory stimuli are presented. In this study, we administered noxious mechanical stimuli to individuals with congenital insensitivity to pain and sampled their brain activity with fMRI. Loss-of-function SCN9A mutations in these individuals abolishes sensory neuron sodium channel Nav1.7 activity, resulting in pain insensitivity through an impaired peripheral drive that leaves tactile percepts fully intact.5 This allows complete experimental disambiguation of sensory responses and painful sensation