Neuron-immune mechanisms contribute to pain in early stages of arthritis

Background: Rheumatoid arthritis (RA) patients frequently show weak correlations between the magnitude of pain and inflammation suggesting that mechanisms other than overt peripheral inflammation contribute to pain in RA. We assessed changes in microglial reactivity and spinal excitability and their contribution to pain-like behaviour in the early stages of collagen-induced arthritis (CIA) model. Methods: Mechanically evoked hypersensitivity, spinal nociceptive withdrawal reflexes (NWRs) and hind paw swelling were evaluated in female Lewis rats before and until 13 days following collagen immunization. In the spinal dorsal horn, microgliosis was assayed using immunohistochemistry (Iba-1/p-p38) and cyto(chemo)kine levels in the cerebrospinal fluid (CSF). Intrathecal administration of microglia-targeting drugs A-438079 (P2X7 antagonist) and LHVS (cathepsin S inhibitor) were examined upon hypersensitivity, NWRs, microgliosis andcyto(chemo)kine levels in the early phase of CIA. Results: The early phase of CIA was associated with mechanical allodynia and exaggerated mechanically evoked spinal NWRs, evident before hind paw swelling, and exacerbated with the development of swelling. Concomitant with the development of hypersensitivity was the presence of reactive spinal microgliosis and an increase of IL-1β levels in CSF (just detectable in plasma). Prolonged intrathecal administration of microglial inhibitors attenuated the development of mechanical allodynia, reduced microgliosis and attenuated IL-1β increments. Acute spinal application of either microglial inhibitor significantly diminished the sensitization of the spinal NWRs. Conclusions: Mechanical hypersensitivity in the early phase of CIA is associated with central sensitization that is dependent upon microglial-mediated release of IL-1β in the spinal cord. Blockade of these spinal events may provide pain relief in RA patients

A quantification of the relationship between neuronal responses in the rat rostral ventromedial medulla and noxious stimulation-evoked withdrawal reflexes

The rostral ventromedial medulla (RVM) regulates a range of involuntary behaviours but is most often associated with nociception via the action of pronociceptive ON cells and antinociceptive OFF cells. The phasic responses of ON and OFF cells determine whether or not incoming noxious signals provoke a withdrawal reflex, and previous studies have suggested that reflex RVM activity patterns actively shape motor output. Here we challenged the model by using juvenile rats, which are known to exhibit markedly different reflex responses compared with adults. By recording single-cell activity in the RVM and the electromyography responses of hindlimb flexor muscles to noxious thermal stimulation we found that the juvenile reflex had a shorter onset latency, was larger in amplitude and exhibited a decreased rise time compared with the adult reflex. The responses of ON and OFF cells faithfully tracked the shorter onset latency of the reflex by also responding earlier and, thus, still preceded the reflex. However, neither the reflex amplitude nor the ongoing response profile was predicted by the firing rate of RVM cells in either age group. Instead we found a close correspondence between RVM activity and the reflex only during the initiation of the response. Furthermore, the short rise time of the juvenile reflex was reflected in higher rates of change of both ON and OFF cell firing. Our data suggest that the RVM is associated only with the initiation of reflexes and does not shape ongoing muscle activity, which is more likely to be subserved by downstream spinal processes

Differential contributions of peripheral and central mechanisms to pain in a rodent model of osteoarthritis

The mechanisms underlying the transition from acute nociceptive pain to centrally maintained chronic pain are not clear. We have studied the contributions of the peripheral and central nervous systems during the development of osteoarthritis (OA) pain. Male Sprague-Dawley rats received unilateral intra-articular injections of monosodium iodoacetate (MIA 1mg) or saline, and weight bearing (WB) asymmetry and distal allodynia measured. Subgroups of rats received intra-articular injections of, QX-314 (membrane impermeable local anaesthetic)+capsaicin, QX-314, capsaicin or vehicle on days 7, 14 or 28 post-MIA and WB and PWT remeasured. On days 7&14 post-MIA, but not day 28, QX-314+capsaicin signfcantly attenuated changes in WB induced by MIA, illustrating a crucial role for TRPV1 expressing nociceptors in early OA pain. The role of top-down control of spinal excitability was investigated. The mu-opioid receptor agonist DAMGO was microinjected into the rostroventral medulla, to activate endogenous pain modulatory systems, in MIA and control rats and refex excitability measured using electromyography. DAMGO (3ng) had a signifcantly larger inhibitory effect in MIA treated rats than in controls. These data show distinct temporal contribtuions of TRPV1 expressing nociceptors and opioidergic pain control systems at later timepoints

Stroking modulates noxious-evoked brain activity in human infants

A subclass of C fibre sensory neurons found in hairy skin are activated by gentle touch [1] and respond optimally to stroking at ∼1–10 cm/s, serving a protective function by promoting affiliative behaviours. In adult humans, stimulation of these C-tactile (CT) afferents is pleasant, and can reduce pain perception [2]. Touch-based techniques, such as infant massage and kangaroo care, are designed to comfort infants during procedures, and a modest reduction in pain-related behavioural and physiological responses has been observed in some studies [3]. Here, we investigated whether touch can reduce noxious-evoked brain activity. We demonstrate that stroking (at 3 cm/s) prior to an experimental noxious stimulus or clinical heel lance can attenuate noxious-evoked brain activity in infants. CT fibres may represent a biological target for non-pharmacological interventions that modulate pain in early life

GPML: an XML-based standard for the interchange of genetic programming trees

We propose a Genetic Programming Markup Language (GPML), an XML based standard for the interchange of genetic programming trees, and outline the benefits such a format would bring in allowing the deployment of trained genetic programming (GP) models in applications as well as the subsidiary benefit of allowing GP researchers to directly share trained trees. We present a formal definition of this standard and describe details of an implementation. In addition, we present a case study where GPML is used to implement a model predictive controller for the control of a building heating plant

Overcoming the barriers to greater public engagement

Integrating science communication training into an undergraduate research project encourages greater academic involvement in public engagement, maximizes audience size, and provides high-quality research data

Riparian thermal conditions across a mixed rural and urban landscape

Riparian corridors have the potential to function as thermal refuges, moderating extremes of local temperature variation. However, although demonstrated at individual sites, and over short periods, the consistency of this effect at wider temporal and spatial scales is poorly understood. The aim of this study is to assess the temperature differences between riparian corridors and adjacent non-riparian habitats and to explore the influence of environmental characteristics on these differences. Air temperature was monitored hourly at 20 paired locations (riparian and non-riparian) for two consecutive years. Urban index and canopy cover were characterised by calculating the percentage of impervious surface area and tree canopy cover within a 100 m radius from the centre of each sampling site. Canopy cover reduced summer thermal stresses in both urban and rural areas whereas high urban index tended to increase the daily thermal indices. Rivers had a significant mitigating effect on the urban riparian thermal condition, particularly in extreme hot weather. Riparian corridors were generally 1 °C cooler than non-riparian locations in summer and could be up to 3 °C cooler at some sites in extreme hot weather. Furthermore, riparian corridors at some sites were warmer than non-riparian locations in winter. These findings suggest that the proximity of rivers can modify riparian thermal environments, potentially reducing the heat stress of riparian corridors across landscapes

Increased function of pronociceptive TRPV1 at the level of the joint in a rat model of osteoarthritis pain

Objectives Blockade of transient receptor potential vanilloid 1 (TRPV1) with systemic antagonists attenuates osteoarthritis (OA) pain behaviour in rat models, but on-target-mediated hyperthermia has halted clinical trials. The present study investigated the potential for targeting TRPV1 receptors within the OA joint in order to produce analgesia. Methods The presence of TRPV1 receptors in human synovium was detected using western blotting and immunohistochemistry. In a rat model of OA, joint levels of an endogenous ligand for TRPV1, 12- ydroxyeicosatetraenoic acid (12-HETE), were quantified using liquid chromatography-tandem mass spectrometry (LCMS/MS). Effects of peripheral administration of the TRPV1 receptor antagonist JNJ-17203212 on afferent fibre activity, pain behaviour and core body temperature were investigated. Effects of a spinal administration of JNJ-17203212 on dorsal horn neuronal responses were studied. Results We demonstrate increased TRPV1 immunoreactivity in human OA synovium, confirming the diseased joint as a potential therapeutic target for TRPV1-mediated analgesia. In a model of OA pain, we report increased joint levels of 12-HETE, and the sensitisation of joint afferent neurones to mechanical stimulation of the knee. Local administration of JNJ- 17203212 reversed this sensitisation of joint afferents and inhibited pain behaviour (weight-bearing asymmetry), to a comparable extent as systemic JNJ- 17203212, in this model of OA pain, but did not alter core body temperature. There was no evidence for increased TRPV1 function in the spinal cord in this model of OA pain. Conclusions Our data provide a clinical and mechanistic rationale for the future investigation of the therapeutic benefits of intra-articular administration of TRPV1 antagonists for the treatment of OA pain

Anxiety enhances pain in a model of osteoarthritis and is associated with altered endogenous opioid function and reduced opioid analgesia

Introduction: Negative affect, including anxiety and depression, is prevalent in chronic pain states such as osteoarthritis (OA) and associated with greater use of opioid analgesics, potentially contributing to present and future opioid crises.Objectives: We tested the hypothesis that the interaction between anxiety, chronic pain, and opioid use results from altered endogenous opioid function.Methods: A genetic model of negative affect, the Wistar–Kyoto (WKY) rat, was combined with intra-articular injection of monosodium iodoacetate (MIA; 1 mg) to mimic clinical presentation. Effects of systemic morphine (0.5–3.5 mg·kg−1) on pain behaviour and spinal nociceptive neuronal activity were compared in WKY and normo-anxiety Wistar rats 3 weeks after MIA injection. Endogenous opioid function was probed by the blockade of opioid receptors (0.1–1 mg·kg−1 systemic naloxone), quantification of plasma β-endorphin, and expression and phosphorylation of spinal mu-opioid receptor (MOR).Results: Monosodium iodoacetate–treated WKY rats had enhanced OA-like pain, blunted morphine-induced analgesia, and greater mechanical hypersensitivity following systemic naloxone, compared with Wistar rats, and elevated plasma β-endorphin levels compared with saline-treated WKY controls. Increased MOR phosphorylation at the master site (serine residue 375) in the spinal cord dorsal horn of WKY rats with OA-like pain (P = 0.0312) indicated greater MOR desensitization.Conclusions: Reduced clinical analgesic efficacy of morphine was recapitulated in a model of high anxiety and OA-like pain, in which endogenous opioid tone was altered, and MOR function attenuated, in the absence of previous exogenous opioid ligand exposure. These findings shed new light on the mechanisms underlying the increased opioid analgesic use in high anxiety patients with chronic pain