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      Functional dichotomy in spinal- vs prefrontal-projecting locus coeruleus modules splits descending noradrenergic analgesia from ascending aversion and anxiety in rats

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          Abstract

          The locus coeruleus (LC) projects throughout the brain and spinal cord and is the major source of central noradrenaline. It remains unclear whether the LC acts functionally as a single global effector or as discrete modules. Specifically, while spinal-projections from LC neurons can exert analgesic actions, it is not known whether they can act independently of ascending LC projections. Using viral vectors taken up at axon terminals, we expressed chemogenetic actuators selectively in LC neurons with spinal ( LC :SC ) or prefrontal cortex ( LC :PFC ) projections. Activation of the LC :SC module produced robust, lateralised anti-nociception while activation of LC :PFC produced aversion. In a neuropathic pain model, LC :SC activation reduced hind-limb sensitisation and induced conditioned place preference. By contrast, activation of LC :PFC exacerbated spontaneous pain, produced aversion and increased anxiety-like behaviour. This independent, contrasting modulation of pain-related behaviours mediated by distinct noradrenergic neuronal populations provides evidence for a modular functional organisation of the LC.

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          Most cited references57

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          Descending control of pain.

          Upon receipt in the dorsal horn (DH) of the spinal cord, nociceptive (pain-signalling) information from the viscera, skin and other organs is subject to extensive processing by a diversity of mechanisms, certain of which enhance, and certain of which inhibit, its transfer to higher centres. In this regard, a network of descending pathways projecting from cerebral structures to the DH plays a complex and crucial role. Specific centrifugal pathways either suppress (descending inhibition) or potentiate (descending facilitation) passage of nociceptive messages to the brain. Engagement of descending inhibition by the opioid analgesic, morphine, fulfils an important role in its pain-relieving properties, while induction of analgesia by the adrenergic agonist, clonidine, reflects actions at alpha(2)-adrenoceptors (alpha(2)-ARs) in the DH normally recruited by descending pathways. However, opioids and adrenergic agents exploit but a tiny fraction of the vast panoply of mechanisms now known to be involved in the induction and/or expression of descending controls. For example, no drug interfering with descending facilitation is currently available for clinical use. The present review focuses on: (1) the organisation of descending pathways and their pathophysiological significance; (2) the role of individual transmitters and specific receptor types in the modulation and expression of mechanisms of descending inhibition and facilitation and (3) the advantages and limitations of established and innovative analgesic strategies which act by manipulation of descending controls. Knowledge of descending pathways has increased exponentially in recent years, so this is an opportune moment to survey their operation and therapeutic relevance to the improved management of pain.
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            A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia.

            A method to measure cutaneous hyperalgesia to thermal stimulation in unrestrained animals is described. The testing paradigm uses an automated detection of the behavioral end-point; repeated testing does not contribute to the development of the observed hyperalgesia. Carrageenan-induced inflammation resulted in significantly shorter paw withdrawal latencies as compared to saline-treated paws and these latency changes corresponded to a decreased thermal nociceptive threshold. Both the thermal method and the Randall-Selitto mechanical method detected dose-related hyperalgesia and its blockade by either morphine or indomethacin. However, the thermal method showed greater bioassay sensitivity and allowed for the measurement of other behavioral parameters in addition to the nociceptive threshold.
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              CRH Engagement of the Locus Coeruleus Noradrenergic System Mediates Stress-Induced Anxiety.

              The locus coeruleus noradrenergic (LC-NE) system is one of the first systems engaged following a stressful event. While numerous groups have demonstrated that LC-NE neurons are activated by many different stressors, the underlying neural circuitry and the role of this activity in generating stress-induced anxiety has not been elucidated. Using a combination of in vivo chemogenetics, optogenetics, and retrograde tracing, we determine that increased tonic activity of the LC-NE system is necessary and sufficient for stress-induced anxiety and aversion. Selective inhibition of LC-NE neurons during stress prevents subsequent anxiety-like behavior. Exogenously increasing tonic, but not phasic, activity of LC-NE neurons is alone sufficient for anxiety-like and aversive behavior. Furthermore, endogenous corticotropin-releasing hormone(+) (CRH(+)) LC inputs from the amygdala increase tonic LC activity, inducing anxiety-like behaviors. These studies position the LC-NE system as a critical mediator of acute stress-induced anxiety and offer a potential intervention for preventing stress-related affective disorders.
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                Author and article information

                Contributors
                Role: Reviewing Editor
                Journal
                eLife
                Elife
                eLife
                eLife
                eLife Sciences Publications, Ltd
                2050-084X
                13 October 2017
                2017
                : 6
                : e29808
                Affiliations
                [1 ]deptSchool of Physiology, Pharmacology and Neuroscience University of Bristol BristolUnited Kingdom
                [2 ]deptMedical School University of Exeter ExeterUnited Kingdom
                [3 ]deptIGMM CNRS, University of Montpellier MontpellierFrance
                University of California, San Francisco United States
                University of California, San Francisco United States
                Author information
                http://orcid.org/0000-0003-0345-0456
                Article
                29808
                10.7554/eLife.29808
                5653237
                29027903
                3d2cd1b4-0975-4e95-a345-a986644baa96
                © 2017, Hirschberg et al

                This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

                History
                : 21 June 2017
                : 11 October 2017
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100010269, Wellcome;
                Award ID: gr088373
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100000883, University of Bristol;
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100004410, European Molecular Biology Organization;
                Award Recipient :
                The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
                Categories
                Research Article
                Neuroscience
                Custom metadata
                The locus coeruleus is organised into functional modules with subsets of noradrenergic neurones independently projecting to the spinal cord and prefrontal cortex to exert discrete, antithetical modulatory actions on a range of pain-related behaviours.

                Life sciences
                noradrenaline,locus coeruleus,pain,endogenous analgesia,chemogenetics,attention,rat
                Life sciences
                noradrenaline, locus coeruleus, pain, endogenous analgesia, chemogenetics, attention, rat

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