Spinal histamine in attenuation of mechanical hypersensitivity in the spinal nerve ligation-induced model of experimental neuropathy

Here we studied whether and through which mechanisms spinal administration of histamine dihydrochloride (histamine) attenuates pain behavior in neuropathic animals. Experiments were performed in rats with spinal nerve ligation-induced neuropathy and a chronic intrathecal catheter for spinal drug delivery. Mechanical hypersensitivity was assessed with monofilaments while radiant heat was used for assessing nociception. Ongoing neuropathic pain and its attenuation by histamine was assessed using conditioned place-preference test. Following spinal administration, histamine at doses 0.1-10 mu g produced a dose-related mechanical antihypersensitivity effect. With prolonged treatment (twice daily 10 mu g for five days), the antihypersensitivity effect of spinal histamine was reduced. In place-preference test, neuropathic animals preferred the chamber paired with histamine (10 mu g). Histamine (10 mu g) failed to influence heat nociception in neuropathic animals or mechanically induced pain behavior in a group of healthy control rats. Histamine-induced mechanical antihypersensitivity effect was prevented by spinal pretreatment with zolantidine (histamine H-2 receptor antagonist), prazosine (alpha(1)-adrenoceptor antagonist) and bicuculline (gamma-aminobutyric acid subtype A, GABA(A), receptor antagonist), but not by pyrilamine (histamine H-1 receptor antagonist), atipamezole (alpha(2)-adrenoceptor antagonist), or raclopride (dopamine D-2 receptor antagonist). A-960656, a histamine H-3 receptor antagonist alone that presumably increased endogenous histamine levels reduced hypersensitivity. Additionally, histamine prevented central (presumably postsynaptically-induced) facilitation of hypersensitivity induced by N-methyl-n-aspartate. The results indicate that spinal histamine at the dose range of 0.1-10 mu g selectively attenuates mechanical hypersensitivity and ongoing pain in neuropathy. The spinal histamine-induced antihypersensitivity effect involves histamine H-2 and GABA(A) receptors and (presumably neuropathy-induced) co-activation of spinal al-adrenoceptors. (C) 2015 Elsevier B.V. All rights reserved.Peer reviewe

Neurophysiological response properties of medullary pain-control neurons following chronic treatment with morphine or oxycodone : modulation by acute ketamine

Descending facilitatory circuitry that involves the rostroventromedial medulla (RVM) exerts a significant role in the development of antinociceptive tolerance and hyperalgesia following chronic morphine treatment. The role of the RVM in the development of antinociceptive tolerance to oxycodone, another clinically used strong opioid. is not yet known. Ketamine, an N-methyl-o-aspartate (NMDA) receptor antagonist, attenuates opioid antinociceptive tolerance, but its effect on RVM cell discharge in opioid-tolerant animals is not known. Here, we compared chronic effects of morphine and oxycodone on the discharge properties of RVM cells and attempted to attenuate chronic treatment-induced changes with ketamine. Parallel recordings of RVM cell discharge and limb withdrawal response were performed under light pentobarbital anesthesia in male rats following sustained systemic treatment with morphine or oxycodone at equianalgesic doses. Ongoing activity and the response to noxious heat and pinch were determined in pronociceptive RVM ON-cells and antinociceptive OFF-cells on the sixth treatment day. Proportions of RVM cell types were not changed. Chronic oxycodone induced antinociceptive tolerance both in limb withdrawal and RVM cell activity. Chronic morphine induced antinociceptive tolerance in limb withdrawal that was accompanied by pronociceptive heat response changes in RVM ON- and OFF-cells. A behaviorally subantinociceptive dose of acute ketamine reversed antinociceptive tolerance both to morphine and oxycodone in limb withdrawal and reversed the chronic morphine-induced pronociceptive discharge changes in RVM cells. The results indicate that an NMDA receptor-dependent descending pronociceptive circuitry involving the RVM has an important role in behavioral antinociceptive tolerance to morphine but not oxycodone. NEW & NOTEWORTHY Morphine and oxycodone are two clinically used strong opioids. Chronic treatment with oxycodone as well as morphine can lead to analgesic tolerance and paradoxical hyperalgesia. Here we show that an N-methyl-n-aspartate receptor-dependent pronociceptive change in discharge properties of rostroventromedial medullary neurons controlling spinal nociception has an important role in antinociceptive tolerance to morphine but not oxycodone. Interestingly, chronic oxycodone did not induce pronociceptive changes in the rostroventromedial medulla.Peer reviewe

Galanin-Mediated Behavioural Hyperalgesia from the Dorsomedial Nucleus of the Hypothalamus Involves Two Independent Descending Pronociceptive Pathways

Activation of the dorsomedial nucleus of the hypothalamus (DMH) by galanin (GAL) induces behavioural hyperalgesia. Since DMH neurones do not project directly to the spinal cord, we hypothesized that the medullary dorsal reticular nucleus (DRt), a pronociceptive region projecting to the spinal dorsal horn (SDH) and/or the serotoninergic raphe-spinal pathway acting on the spinal 5-HT3 receptor (5HT(3)R) could relay descending nociceptive facilitation induced by GAL in the DMH. Heat-evoked paw-withdrawal latency (PWL) and activity of SDH neurones were assessed in monoarthritic (ARTH) and control (SHAM) animals after pharmacological manipulations of the DMH, DRt and spinal cord. The results showed that GAL in the DMH and glutamate in the DRt lead to behavioural hyperalgesia in both SHAM and ARTH animals, which is accompanied particularly by an increase in heat-evoked responses of wide-dynamic range neurons, a group of nociceptive SDH neurones. Facilitation of pain behaviour induced by GAL in the DMH was reversed by lidocaine in the DRt and by ondansetron, a 5HT(3)R antagonist, in the spinal cord. However, the hyperalgesia induced by glutamate in the DRt was not blocked by spinal ondansetron. In addition, in ARTH but not SHAM animals PWL was increased after lidocaine in the DRt and ondansetron in the spinal cord. Our data demonstrate that GAL in the DMH activates two independent descending facilitatory pathways: (i) one relays in the DRt and (ii) the other one involves 5-HT neurones acting on spinal 5HT(3)Rs. In experimental ARTH, the tonic pain-facilitatory action is increased in both of these descending pathways.Peer reviewe

Antagonism of peripheral opioid receptors by methylnaltrexone does not prevent morphine tolerance in rats

Opioids are effective analgesics in the management of severe pain. However, tolerance, leading to dose escalation and adverse effects are significant limiting factors in their use. The role of peripheral opioid receptors in analgesia has been discussed especially under inflammatory conditions. The results from pharmacological and conditional knockout studies together do not provide a clear picture of the contribution of peripheral opioid receptors on antinociceptive tolerance and this needs to be evaluated. Therefore, we studied whether the peripherally restricted opioid receptor antagonist, methylnaltrexone (MNTX), could prevent morphine tolerance without attenuating the antinociceptive effect of morphine. Male Sprague-Dawley rats were treated for 7 days with increasing subcutaneous doses of morphine (5-30 mg/kg) and were coadministered saline, MNTX (0.5 or 2 mg/kg), or naltrexone (NTX; 2 mg/kg). Nociception was assessed with tail-flick, hotplate, and von Frey tests. Morphine, MNTX, and NTX concentrations in the plasma, brain, and spinal cord were measured by liquid chromatography-tandem mass spectrometry. In acute coadministration, NTX, but not MNTX, abolished the acute antinociceptive effects of morphine in all nociceptive tests. The antinociceptive tolerance after repeated morphine administration was also prevented by NTX but not by MNTX. MNTX penetrated to the spinal cord and the brain to some extent after repeated administration. The results do not support the use of MNTX for preventing opioid tolerance and also suggest that morphine tolerance is mediated by central rather than peripheral opioid receptors in the rat.Peer reviewe

Morphine-3-glucuronide causes antinociceptive cross-tolerance to morphine and increases spinal substance P expression

Morphine-3-glucuronide (M3G), the main metabolite of morphine, has been implicated in the development of tolerance and of opioid-induced hyperalgesia, both limiting the analgesic use of morphine. We evaluated the acute and chronic effects of M3G and morphine as well as development of antinociceptive cross-tolerance between morphine and M3G after intrathecal administration and assessed the expression of pain-associated neurotransmitter substance P in the spinal cord. Sprague-Dawley rats received intrathecal M3G or morphine twice daily for 6 days. Nociception and tactile allodynia were measured with von Frey filaments after acute and chronic treatments. Substance P levels in the dorsal horn of the spinal cord were determined by immunohistochemistry after 4-day treatments. Acute morphine caused antinociception as expected, whereas acute M3G caused tactile allodynia, as did both chronic M3G and morphine. Chronic M3G also induced antinociceptive cross-tolerance to morphine. M3G and morphine increased substance P levels similarly in the nociceptive laminae of the spinal cord. This study shows that chronic intrathecal M3G sensitises animals to mechanical stimulation and elevates substance P levels in the nociceptive laminae of the spinal cord. Chronic M3G also induces antinociceptive cross-tolerance to morphine. Thus, chronic M3G exposure might contribute to morphine-induced tolerance and opioid-induced hyperalgesia.Peer reviewe

Novel RET agonist for the treatment of experimental neuropathies

The glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) alleviate symptoms of experimental neuropathy, protect and stimulate regeneration of sensory neurons in animal models of neuropathic pain, and restore their functional activity. However, clinical development of GFL proteins is complicated by their poor pharmacokinetic properties and multiple effects mediated by several receptors. Previously, we have identified a small molecule that selectively activates the major signal transduction unit of the GFL receptor complex, receptor tyrosine kinase RET, as an alternative to GFLs, for the treatment of neuropathic pain. We then introduced a series of chemical changes to improve the biological activity of these compounds and tested an optimized compound named BT44 in a panel of biological assays. BT44 efficiently and selectively stimulated the GFL receptor RET and activated the intracellular mitogene-activated protein kinase/extracellular signal-regulated kinase pathway in immortalized cells. In cultured sensory neurons, BT44 stimulated neurite outgrowth with an efficacy comparable to that of GFLs. BT44 alleviated mechanical hypersensitivity in surgery- and diabetes-induced rat models of neuropathic pain. In addition, BT44 normalized, to a certain degree, the expression of nociception-related neuronal markers which were altered by spinal nerve ligation, the neuropathy model used in this study. Our results suggest that the GFL mimetic BT44 is a promising new lead for the development of novel disease-modifying agents for the treatment of neuropathy and neuropathic pain.Peer reviewe

Responses of the atmospheric concentration of radon-222 to the vertical mixing and spatial transportation

Radon-222 (Rn-222) has traditionally been used as an atmospheric tracer for studying air masses and planetary boundary-layer evolution. However, there are various factors that influence its atmospheric concentration. Therefore, we investigated the variability of the atmospheric radon concentration in response to the vertical air mixing and spatial transport in a boreal forest environment in northern Europe. Long-term Rn-222 data collected at the SMEAR II station in southern Finland during 2000-2006 were analysed along with meteorological data, mixing layer height retrievals and air-mass back trajectory information. The daily mean atmospheric radon concentration followed a log-normal distribution within the range <0.1-11 Bq m(-3), with the geometric mean of 2.5 Bq m(-3) and a geometric standard deviation of 1.7 Bq m(3). In spring, summer, autumn and winter, the daily mean concentrations were 1.7, 2.7, 2.8 and 2.7 Bq m(-3), respectively. The low, spring radon concentration was especially attributed to the joint effect of enhanced vertical mixing due to the increasing solar irradiance and inhibited local emissions due to snow thawing. The lowest atmospheric radon concentration was observed with northwesterly winds and high radon concentrations with southeasterly winds, which were associated with the marine and continental origins of air masses, respectively. The atmospheric radon concentration was in general inversely proportional to the mixing layer height. However, the ambient temperature and small-scale turbulent mixing were observed to disturb this relationship. The evolution of turbulence within the mixing layer was expected to be a key explanation for the delay in the response of the atmospheric radon concentration to the changes in the mixing layer thickness. Radon is a valuable naturally-occurring tracer for studying boundary layer mixing processes and transport patterns, especially when the mixing layer is fully developed. However, complementing information, provided by understanding the variability of the atmospheric radon concentration, is of high necessity to be taken into consideration for realistically interpreting the evolution of air masses or planetary boundary layer.Peer reviewe

Differential Spinal and Supraspinal Activation of Glia in a Rat Model of Morphine Tolerance

Development of tolerance is a well known pharmacological characteristic of opioids and a major clinical problem. In addition to the known neuronal mechanisms of opioid tolerance, activation of glia has emerged as a potentially significant new mechanism. We studied activation of microglia and astrocytes in morphine tolerance and opioid-induced hyperalgesia in rats using immunohistochemistry, flow cytometry and RNA sequencing in spinal-and supraspinal regions. Chronic morphine treatment that induced tolerance and hyperalgesia also increased immunoreactivity of spinal microglia in the dorsal and ventral horns. Flow cytometry demonstrated that morphine treatment increased the proportion of M2-polarized spinal microglia, but failed to impact the number or the proportion of M1-polarized microglia. In the transcriptome of microglial cells isolated from the spinal cord (SC), morphine treatment increased transcripts related to cell activation and defense response. In the studied brain regions, no activation of microglia or astrocytes was detected by immunohistochemistry, except for a decrease in the number of microglial cells in the substantia nigra. In flow cytometry, morphine caused a decrease in the number of microglial cells in the medulla, but otherwise no change was detected for the count or the proportion of M1-and M2-polarized microglia in the medulla or sensory cortex. No evidence for the activation of glia in the brain was seen. Our results suggest that glial activation associated with opioid tolerance and opioid-induced hyperalgesia occurs mainly at the spinal level. The transcriptome data suggest that the microglial activation pattern after chronic morphine treatment has similarities with that of neuropathic pain. (C) 2018 IBRO. Published by Elsevier Ltd. All rights reserved.Peer reviewe

Conceptual design of a measurement network of the global change

The global environment is changing rapidly due to anthropogenic emissions and actions. Such activities modify aerosol and greenhouse gas concentrations in the atmosphere, leading to regional and global climate change and affecting, e.g., food and fresh-water security, sustainable use of natural resources and even demography. Here we present a conceptual design of a global, hierarchical observation network that can provide tools and increased understanding to tackle the inter-connected environmental and societal challenges that we will face in the coming decades. The philosophy behind the conceptual design relies on physical conservation laws of mass, energy and momentum, as well as on concentration gradients that act as driving forces for the atmosphere-biosphere exchange. The network is composed of standard, flux and/or advanced and flagship stations, each of which having specific and identified tasks. Each ecosystem type on the globe has its own characteristic features that have to be taken into consideration. The hierarchical network as a whole is able to tackle problems related to large spatial scales, heterogeneity of ecosystems and their complexity. The most comprehensive observations are envisioned to occur in flagship stations, with which the process-level understanding can be expanded to continental and global scales together with advanced data analysis, Earth system modelling and satellite remote sensing. The denser network of the flux and standard stations allows application and up-scaling of the results obtained from flagship stations to the global level.Peer reviewe

Finnish Centre of Excellence in Physics, Chemistry, Biology and Meteorology of Atmospheric Composition and Climate Change : summary and outlook

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