Chloride-dependent mechanisms of multimodal sensory discrimination and neuropathic sensitization in Drosophila

AbstractIndividual sensory neurons can be tuned to many stimuli, each driving unique, stimulus-relevant behaviors, and the ability of multimodal nociceptor neurons to discriminate between potentially harmful and innocuous stimuli is broadly important for organismal survival. Moreover, disruptions in the capacity to differentiate between noxious and innocuous stimuli can result in neuropathic pain. Drosophila larval Class III (CIII) neurons are peripheral noxious cold nociceptors and gentle touch mechanosensors; high levels of activation drive cold-evoked contraction (CT) behavior, while low levels of activation result in a suite of touch-associated behaviors. However, it is unknown what molecular factors underlie CIII multimodality. Here, we show that the TMEM16/anoctamins subdued and white walker (wwk; CG15270) are required for cold-evoked CT, but not for touch-associated behavior, indicating a conserved role for anoctamins in nociception. We also evidence that CIII neurons make use of atypical depolarizing chloride currents to encode cold, and that overexpression of ncc69—a fly homologue of NKCC1—results in phenotypes consistent with neuropathic sensitization, including behavioral hypersensitization and spontaneous nociceptor activity, making Drosophila CIII neurons a candidate system for future studies of the basic mechanisms underlying neuropathic pain.

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Biomarkers for microglia activation in neuropathic pain

Anaesthesia, Pain & Intensive Care ◽

10.35975/apic.v24i1.1229 ◽

2020 ◽

Vol 24 (1) ◽

pp. 87-93

Author(s):

Putu Eka Widyadharma ◽

Aurelia Vania ◽

Jimmy FA Barus ◽

Yudiyanta . ◽

Thomas Eko Purwata

Keyword(s):

Neuropathic Pain ◽

Intensive Care ◽

Microglia Activation ◽

Future Research ◽

Future Studies ◽

Activated Microglia ◽

New Therapy ◽

Promising Target ◽

Chemical Mediators

Neuropathic pain (NP) is a result of direct disturbances of somatosensory pathways. Its pathophysiology includes various mechanisms. Recent studies have reported an important role of microglia in the NP mechanism. There are several chemical molecules which are involved in microglia activation. The activated microglia will, in turn, enhance some receptors expression that can be used as markers of its activation. Though we still need future studies about precise microglia role in NP mechanism, the chemical mediators that initiate microglia activation and the alteration of some receptors in the activated microglia which have been found from previous studies can be the interesting future research materials and the promising target for a new therapy for NP. Citation: Widyadharma PE, Vania A, Barus JFA, Yudiyanta, Purwata TE. Biomarkers for microglia activation in neuropathic pain. Anaesth pain intensive care 2020;24(1):___ DOI: https://doi.org/10.35975/apic.v24i1. Received – 12 June 2019, Reviewed – 15 September 2019, 29 February 2020, Accepted – 2 March 2020;

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Sensory Neurons, Ion Channels, Inflammation and the Onset of Neuropathic Pain

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/s0317167100013937 ◽

2012 ◽

Vol 39 (4) ◽

pp. 416-435 ◽

Cited By ~ 46

Author(s):

Patrick L. Stemkowski ◽

Peter A. Smith

Keyword(s):

Spinal Cord ◽

Neuropathic Pain ◽

Peripheral Neuropathy ◽

Pain Management ◽

Sensory Neurons ◽

Inflammatory Mediators ◽

Primary Afferents ◽

Ectopic Activity ◽

Management Procedures

Neuropathic pain often fails to respond to conventional pain management procedures. here we review the aetiology of neuropathic pain as would result from peripheral neuropathy or injury. We show that inflammatory mediators released from damaged nerves and tissue are responsible for triggering ectopic activity in primary afferents and that this, in turn, provokes increased spinal cord activity and the development of ‘central sensitization’. Although evidence is mounting to support the role of interleukin-1β, prostaglandins and other cytokines in the onset of neuropathic pain, the clinical efficacy of drugs which antagonize or prevent the actions of these mediators is yet to be determined. basic science findings do, however, support the use of pre-emptive analgesia during procedures which involve nerve manipulation and the use of anti-inflammatory steroids as soon as possible following traumatic nerve injury.

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Toll-like receptor 7 contributes to neuropathic pain by activating NF-κB in primary sensory neurons

Brain Behavior and Immunity ◽

10.1016/j.bbi.2020.03.019 ◽

2020 ◽

Vol 87 ◽

pp. 840-851 ◽

Cited By ~ 5

Author(s):

Long He ◽

Guang Han ◽

Shaogen Wu ◽

Shibin Du ◽

Yang Zhang ◽

...

Keyword(s):

Neuropathic Pain ◽

Sensory Neurons ◽

Primary Sensory Neurons ◽

Toll Like Receptor

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Novel RET agonist for the treatment of experimental neuropathies

Molecular Pain ◽

10.1177/1744806920950866 ◽

2020 ◽

Vol 16 ◽

pp. 174480692095086 ◽

Cited By ~ 2

Author(s):

Hanna Viisanen ◽

Ulpukka Nuotio ◽

Oleg Kambur ◽

Arun Kumar Mahato ◽

Viljami Jokinen ◽

...

Keyword(s):

Neuropathic Pain ◽

Sensory Neurons ◽

Spinal Nerve ◽

Biological Assays ◽

Neuronal Markers ◽

Extracellular Signal Regulated Kinase ◽

Extracellular Signal ◽

Pharmacokinetic Properties ◽

Immortalized Cells ◽

Disease Modifying Agents

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.

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TET1 Overexpression Mitigates Neuropathic Pain Through Rescuing the Expression of μ-Opioid Receptor and Kv1.2 in the Primary Sensory Neurons

Neurotherapeutics ◽

10.1007/s13311-018-00689-x ◽

2018 ◽

Vol 16 (2) ◽

pp. 491-504 ◽

Cited By ~ 7

Author(s):

Qiang Wu ◽

Guihua Wei ◽

Fengtao Ji ◽

Shushan Jia ◽

Shaogen Wu ◽

...

Keyword(s):

Neuropathic Pain ◽

Opioid Receptor ◽

Sensory Neurons ◽

Primary Sensory Neurons ◽

Μ Opioid Receptor

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Significance of Group Composition for the Welfare of Pastured Horses

Animals ◽

10.3390/ani9010014 ◽

2019 ◽

Vol 9 (1) ◽

pp. 14 ◽

Cited By ~ 2

Author(s):

Hrefna Sigurjónsdóttir ◽

Hans Haraldsson

Keyword(s):

Social Interactions ◽

Group Composition ◽

Peer Groups ◽

Social Contact ◽

Statistical Modelling ◽

Future Studies ◽

Low Levels ◽

Breeding Groups ◽

Young Horses ◽

Icelandic Horses

We explore how herd composition and management factors correlate with frequencies of social interactions in horse groups. Since the welfare of horses correlates with low aggression levels and social contact opportunities, information of this kind is important. The data are a collection of records of social interactions of 426 Icelandic horses in 20 groups of at least eight horses. The complexities and limitations of the data prohibit useful statistical modelling so the results are presented descriptively. Interesting and informative patterns emerge which can be of use both in management and in future studies. Of special interest are the low levels of agonistic behaviours in breeding groups where one stallion was present. The horses were less agonistic when in groups with young foals and where group membership was stable. Unfamiliar yearlings in peer groups were especially aggressive. Allogrooming was most frequent in groups with relatively more young horses and in unstable and small groups. Interestingly, the horses allogroomed more if they had few preferred allogrooming partners. The findings show that composition (age/sex) and stability of groups are of great importance with respect to aggression levels and opportunities for establishing bonds.

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