Actividad del sistema noradrenérgico-locus coeruleus en el dolor neuropático a lo largo del tiempo

El proceso por el que el dolor agudo pasa a ser crónico provoca una remodelación cerebral disfuncional, que se caracteriza por una hipersensibilidad sensorial y la posible aparición de trastornos emocionales, provocando la comorbilidad de ambas patologías (dolor-trastorno emocional). Aunque exista una fuerte comorbilidad entre el dolor crónico y la depresión, el mecanismo por el cual una patología precipita la aparición de la otra sigue sin estar claros. Algunos estudios parecen indicar que el dolor y la depresión inducida por dolor crónico comparten mecanismos neurobiológicos comunes. Por tanto, conocer las bases biológicas que subyacen a esta comorbilidad podría establecer un avance en el diagnóstico y el tratamiento de los pacientes, así como en el desarrollo de futuros enfoques terapéuticos. El locus coeruleus (LC) es la fuente principal de noradrenalina del Sistema Nervioso Central y se conoce en el campo del dolor su papel en la inhibición descendente de la transmisión dolorosa de tipo aguda y por su participación en el proceso atencional ante un estímulo bilógicamente relevante como sería el dolor. Además, su actividad parece estar implicada en la conducta pro-depresiva. Sin embargo, aún se desconoce su papel o el papel de sus proyecciones descendentes y ascendentes en condiciones de dolor crónico, así como su relación con la comorbilidad. Utilizando la lesión unilateral por constricción crónica del nervio ciático como modelo de dolor neuropático, en el estudio I se utilizaron ratas Sprague Dawley macho. En este estudio se han identificado una serie de cambios plásticos en las neuronas del LC dependiente del tiempo desde el inicio de la lesión y en relación con el lugar de la lesión, LC ipsilateral (LCipsi; mismo sitio de la lesión) o LC contralateral (LCcontra; lado contrario de la lesión) en la evaluación de la dimensión sensorial y la sintomatología depresiva. Para modular la actividad del LC se utilizaron aproximaciones farmacológicas convencionales y de farmacogenética mientras los animales eran sometidos a test de conducta nociceptivos durante tres puntos temporales de la neuropatía: corto plazo (2 días después de la lesión), medio plazo (7 días después de la lesión) y largo plazo (28 días después de la lesión) y de evaluación de la sintomatología depresiva a largo plazo (28 días después de la lesión). Los resultados obtenidos mostraron que la inactivación del LCipsi mediante la administración intra-LC de lidocaína aumentó la alodinia al frío 2 días después de la lesión nerviosa, pero no luego. Sin embargo, el bloqueo del LCcontra (siguiendo la misma metodología) redujo la alodinia al frío 7 y 30 días después de inducir neuropatía, pero no antes. Además, el bloqueo con lidocaína del LCipsi o del LCcontra revirtió la conducta pro-depresiva inducida por dolor 30 días después de la neuropatía. Una de las áreas involucradas en el mantenimiento y la amplificación de la señal dolorosa a lo largo del tiempo es el núcleo reticular dorsal (DRt). En este estudio se reportó en animales con dolor a largo plazo un aumento de la expresión de pCREB en el DRtcontra, pero no en el DRtipsi. Además, la inhibición de las proyecciones noradrenérgicas del LCcontra hacía el DRtcontra mediante farmacogenética tuvo un efecto analgésico 30 días después de la lesión. Aunque la inhibición de esta proyección (neuronas noradrenérgicas del LCcontra que proyectan al DRtcontra) si efectuó cambios en la dimensión sensorial no provocó cambios en la conducta pro-depresiva en animales con dolor a largo plazo. Sin embargo, si indujo un comportamiento depresivo en animales sanos (Sham). Los resultados obtenidos mostraron que la lesión nerviosa activa el LCipsi, que amortigua por un corto periodo de tiempo el fenotipo de dolor neuropático. Por otro lado, en el dolor crónico hay una activación de la vía LCcontra- DRtcontra que contribuye a la facilitación del dolor y mantiene el dolor a lo largo del tiempo. En cambio, ambos LC (LCipsi y LCcontra) se activan de manera global contribuyendo así su actividad en el fenotipo depresivo asociado. De igual manera, en el estudio II, utilizando el mismo modelo de dolor neuropático, pero en ratas Long-Evans wild-type y transgénicas TH-CRE, se evaluó la función del LC en relación con el lugar de la lesión (LCipsi o LCcontra) y los diferentes puntos temporales en la conducta sensorial y pro-depresiva. Mediante el uso de la tecnología DREADD y el uso de farmacología convencional se moduló la actividad del LC en los diferentes test conductuales. De esta manera, la inhibición global del LCipsi aumentó la sensibilidad al dolor a corto plazo, pero no después. Sin embargo, bloqueo global de ambos LC de manera unilateral alivió la conducta pro-depresiva inducida por dolor crónico. En ambos estudios se ha demostrado una contribución asimétrica por parte de los módulos del LC a medida que se desarrolla la neuropatía. Posteriormente, se estudió el papel de las proyecciones del LC hacia la SC en la conducta sensorial (de manera unilateral). Se ha demostrado que la vía noradrenérgica LCipsi-SC esta activa en animales con dolor a corto plazo mediante un aumento de los niveles de c-Fos. Por tanto, la inhibición de la vía LCipsi- médula espinal provocó una disminución del umbral del dolor a corto plazo. Por otra parte, la activación quimiogenética de la vía LCipsi-SC si produjo un efecto analgésico en todos los puntos temporales de la neuropatía. Por otro lado, una de las áreas supraespinales que recibe proyecciones noradrenérgicas del LC es la corteza cingulada anterior rostral (CCAr). La CCAr es una de las áreas implicadas en la aparición de la sintomatología pro-depresiva inducida por dolor crónico. En este estudio se ha demostrado que la vía noradrenérgica del LC a la CCAr está activa en animales con dolor a largo plazo mediante a un aumento de los niveles de c-Fos. En consecuencia, la inactivación quimiogenética de la vía noradrenérgica del LC hacia la CCAr revierte la depresión inducida por el dolor a largo plazo, sin afectar a la conducta sensorial evocada. Además, este efecto parece estar mediado por los receptores α1 y α2 de la CCAr. Estos resultados demuestran que el dolor provoca una activación asimétrica de módulos específicos del LC promoviendo un efecto analgésico temprano (dolor agudo) y la aparición del comportamiento depresivo se produce de manera tardía (dolor crónico). Además, se ha demostrado que la vía analgésica deja de ser funcional a medida que el dolor se cronifica. Sin embargo, la activación exógena de esta vía produce analgesia en todos los puntos de la neuropatía

The Role of the Locus Coeruleus in Pain and Associated Stress-Related Disorders

The locus coeruleus (LC)-noradrenergic system is the main source of noradrenaline in the central nervous system and is involved intensively in modulating pain and stress-related disorders (e.g., major depressive disorder and anxiety) and in their comorbidity. However, the mechanisms involving the LC that underlie these effects have not been fully elucidated, in part owing to the technical difficulties inherent in exploring such a tiny nucleus. However, novel research tools are now available that have helped redefine the LC system, moving away from the traditional view of LC as a homogeneous structure that exerts a uniform influence on neural activity. Indeed, innovative techniques such as DREADDs (designer receptors exclusively activated by designer drugs) and optogenetics have demonstrated the functional heterogeneity of LC, and novel magnetic resonance imaging applications combined with pupillometry have opened the way to evaluate LC activity in vivo. This review aims to bring together the data available on the efferent activity of the LC-noradrenergic system in relation to pain and its comorbidity with anxiodepressive disorders. Acute pain triggers a robust LC stress response, producing spinal cord–mediated endogenous analgesia while promoting aversion, vigilance, and threat detection through its ascending efferents. However, this protective biological system fails in chronic pain, and LC activity produces pain facilitation, anxiety, increased aversive memory, and behavioral despair, acting at the medulla, prefrontal cortex, and amygdala levels. Thus, the activation/deactivation of specific LC projections contributes to different behavioral outcomes in the shift from acute to chronic pain

Chemogenetic silencing of the locus coeruleus–basolateral amygdala pathway abolishes pain-induced anxiety and enhanced aversive learning in rats.

BACKGROUND: Pain affects both sensory and emotional aversive responses, often provoking anxiety-related diseases when chronic. However, the neural mechanisms underlying the interactions between anxiety and chronic pain remain unclear. METHODS: We characterized the sensory, emotional, and cognitive consequences of neuropathic pain (chronic constriction injury) in a rat model. Moreover, we determined the role of the locus coeruleus (LC) neurons that project to the basolateral amygdala (BLA) using a DREADD (designer receptor exclusively activated by designer drugs). RESULTS: Chronic constriction injury led to sensorial hypersensitivity in both the short term and long term. Otherwise, long-term pain led to an anxiety-like profile (in the elevated zero maze and open field tests), as well as increased responses to learn aversive situations (in the passive avoidance and fear conditioning tests) and an impairment of non-emotional cognitive tasks (in the novel object recognition and object pattern of separation tests). Chemogenetic blockade of the LC-BLA pathway and intra-BLA or systemic antagonism of beta-adrenergic receptors abolished both long-term pain-induced anxiety and enhanced fear learning. By contrast, chemogenetic activation of this pathway induced anxiety-like behaviors and enhanced the aversive learning and memory index in sham animals, although it had little effect on short- and long-term chronic constriction injury animals. Interestingly, modulation of LC-BLA activity did not modify sensorial perception or episodic memory. CONCLUSIONS: Our results indicate that dimensions associated with pain are processed by independent pathways and that there is an overactivation of the LC-BLA pathway when anxiety and chronic pain are comorbid, which involves the activity of beta-adrenergic receptors

Characterization of a Ferryl Flip in Electronically Tuned Nonheme Complexes. Consequences in Hydrogen Atom Transfer Reactivity

Two oxoiron(IV) isomers (R2a and R2b) of general formula [FeIV(O)(RPyNMe3)(CH3CN)]2+ are obtained by reaction of their iron(II) precursor with NBu4IO4. The two isomers differ in the position of the oxo ligand, cis and trans to the pyridine donor. The mechanism of isomerization between R2a and R2b has been determined by kinetic and computational analyses uncovering an unprecedented path for interconversion of geometrical oxoiron(IV) isomers. The activity of the two oxoiron(IV) isomers in hydrogen atom transfer (HAT) reactions shows that R2a reacts one order of magnitude faster than R2b, which is explained by a repulsive noncovalent interaction between the ligand and the substrate in R2b. Interestingly, the electronic properties of the R substituent in the ligand pyridine ring do not have a significant effect on reaction rates. Overall, the intrinsic structural aspects of each isomer define their relative HAT reactivity, overcoming changes in electronic properties of the ligand.10 página

Pain and depression comorbidity causes asymmetric plasticity in the locus coeruleus neurons

There is strong comorbidity between chronic pain and depression, although the neural circuits and mechanisms underlying this association remain unclear. By combining immunohistochemistry, tracing studies and western blotting, with the use of different DREADDS (designer receptor exclusively activated by designer drugs) and behavioural approaches in a rat model of neuropathic pain (chronic constriction injury), we explore how this comorbidity arises. To this end, we evaluated the time-dependent plasticity of noradrenergic locus coeruleus neurons relative to the site of injury: ipsilateral (LCipsi) or contralateral (LCcontra) locus coeruleus at three different time points: short (2 days), mid (7 days) and long term (30-35 days from nerve injury). Nerve injury led to sensorial hypersensitivity from the onset of injury, whereas depressive-like behaviour was only evident following long-term pain. Global chemogenetic blockade of the LCipsi system alone increased short-term pain sensitivity while the blockade of the LCipsi or LCcontra relieved pain-induced depression. The asymmetric contribution of locus coeruleus modules was also evident as neuropathy develops. Hence, chemogenetic blockade of the LCipsi -> spinal cord projection, increased pain-related behaviours in the short term. However, this lateralized circuit is not universal as the bilateral chemogenetic inactivation of the locus coeruleus-rostral anterior cingulate cortex pathway or the intra-rostral anterior cingulate cortex antagonism of alpha1- and alpha2-adrenoreceptors reversed long-term pain-induced depression. Furthermore, chemogenetic locus coeruleus to spinal cord activation, mainly through LCipsi, reduced sensorial hypersensitivity irrespective of the time post-injury. Our results indicate that asymmetric activation of specific locus coeruleus modules promotes early restorative analgesia, as well as late depressive-like behaviour in chronic pain and depression comorbidity.This study was supported by grants cofinanced by the 'Fondo Europeo de Desarrollo Regional' (FEDER)-UE 'A way to build Europe' from the `Ministerio de Economia y Competitividad' (MINECO: RTI2018-099778-B-I00) and by the 'Ministerio de SaludInstituto de Salud Carlos III' (PI18/01691); the 'Consejeria de Salud de la Junta de Andalucia' (PI-0134-2018); the 'Programa Operativo de Andalucia FEDER, Iniciativa Territorial Integrada ITI 2014-2020 Consejeria Salud, Junta de Andalucia' (PI-0080-2017); the "Consejeri ' a de Transformacion Economica, Industria, Conocimiento y Universidades, Junta de Andalucia" (PEMP-00082020), Instituto de Investigacion e Innovacion en Ciencias Biomedicas de Cadiz (INiBICA LI19/06IN-CO22); the `Consejeri ' a de Economia, Innovacion, Ciencia y Empleo de la Junta de Andalucia' (CTS-510); the 'Centro de Investigacion Biomedica en Red de Salud Mental-CIBERSAM' (CB/07/09/0033) and the Academy of Finland (315043)

Particpación del sistema NE en la expresión de memorias condicionadas asociadas a la administración de cocaína

Treball Final de Grau en Psicologia. Codi: PS1048. Curs 2013-2014It has been proposed that neuroadaptations underlying psychomotor sensitization induced by repeated administration of drugs of abuse are associated with pathological, excessive motivation toward drugs and drug-associated stimuli, and are involved in facilitation and maintenance of addictive behavior. It has been shown that cocaine-induced psychomotor sensitization is sensitive to the effects of conditioning; expression of sensitization appears to be dependent on the context in which it was acquired. In this regard, it has been proposed that cues associated with repeated administration of drugs can trigger motivational states that can in turn facilitate drug seeking and intake. Therefore, conditional effects are important to study in the context of drug addiction. Research focusing on consolidation and expression of memories supporting cueinduced behaviors, is currently paying considerable attention to the noradrenergic (NE) system, and in particular to α₁ and β-adrenergic receptors. First, our studies in the laboratory focused on exploring the effects of propranolol (nonspecific antagonist of b-adrenergic receptors), with prior repeated administration of cocaine / saline (inducing conditioned sensitization) in the same context (CS +). Sensitized animals showed further drug-free, context-dependent hiperactivation, an effect that was prevented by propranolol. The present study further explored the role of NE receptors by using prazosin, a selective α-adrenergic receptors antagonist. Male DBA/2J animals received intraperitoneal injections of 0 or 20 mg/kg of cocaine on alternate days (Mon, Wed, Fri, Mon, Wed, Fri) in order to achieve psychomotor sensitization. Locomotor activity of animals treated with cocaine was always assessed in a chamber with a particular flooring configuration (grid or hole; counterbalanced), CS+. This design was also used for saline treated animals (CS-). On day 15 of the experiment all animals were presented with the CS +; we obtained conditioned hyperactivity in the group previously treated with cocaine. Prazosin did not block this effect. The finals results were that prazosin has no effect on repeated administration of cocaine-induced conditioned hyperactivity

Effect of DSP4 and desipramine in the sensorial and affective component of neuropathic pain in rats

Previous findings suggest that neuropathic pain induces characteristic changes in the noradrenergic system that may modify the sensorial and affective dimensions of pain. We raise the hypothesis that different drugs that manipulate the noradrenergic system can modify specific domains of pain. In the chronic constriction injury (CCI) model of neuropathic pain, the sensorial (von Frey and acetone tests) and the affective (place escape/avoidance paradigm) domains of pain were evaluated in rats 1 and 2weeks after administering the noradrenergic neurotoxin [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride] (DSP4, 50mg/kg). In other animals, we evaluated the effect of enhancing noradrenergic tone in the 2weeks after injury by administering the antidepressant desipramine (10mg/kg/day, delivered by osmotic minipumps) during this period, a noradrenaline reuptake inhibitor. Moreover, the phosphorylation of the extracellular signal regulated kinases (p-ERK) in the anterior cingulate cortex (ACC) was also assessed. The ACC receives direct inputs from the main noradrenergic nucleus, the locus coeruleus, and ERK activation has been related with the expression of pain-related negative affect. These studies revealed that DSP4 almost depleted noradrenergic axons in the ACC and halved noradrenergic neurons in the locus coeruleus along with a decrease in the affective dimension and an increased of p-ERK in the ACC. However, it did not modify sensorial pain perception. By contrast, desipramine reduced pain hypersensitivity, while completely impeding the reduction of the affective pain dimension and without modifying the amount of p-ERK. Together results suggest that the noradrenergic system may regulate the sensorial and affective sphere of neuropathic pain independentl

Nerve injury induces transient locus coeruleus activation over time: role of the locus coeruleus–dorsal reticular nucleus pathway

The transition from acute to chronic pain results in maladaptive brain remodeling, as characterized by sensorial hypersensitivity and the ensuing appearance of emotional disorders. Using the chronic constriction injury of the sciatic nerve as a model of neuropathic pain in male Sprague-Dawley rats, we identified time-dependent plasticity of locus coeruleus (LC) neurons related to the site of injury, ipsilateral (LCipsi) or contralateral (LCcontra) to the lesion, hypothesizing that the LC→dorsal reticular nucleus (DRt) pathway is involved in the pathological nociception associated with chronic pain. LCipsiinactivation with lidocaine increased cold allodynia 2 days after nerve injury but not later. However, similar blockade of LCcontrareduced cold allodynia 7 and 30 days after inducing neuropathy but not earlier. Furthermore, lidocaine blockade of the LCipsior LCcontrareversed pain-induced depression 30 days after neuropathy. Long-Term pain enhances phosphorylated cAMP-response element binding protein expression in the DRtcontrabut not in the DRtipsi. Moreover, inactivation of the LCcontra→DRtcontrapathway using dual viral-mediated gene transfer of designer receptor exclusively activated by designer drugs produced consistent analgesia in evoked and spontaneous pain 30 days postinjury. This analgesia was similar to that produced by spinal activation of α2-Adrenoreceptors. Furthermore, chemogenetic inactivation of the LCcontra→DRtcontrapathway induced depressive-like behaviour in naïve animals, but it did not modify long-Term pain-induced depression. Overall, nerve damage activates the LCipsi, which temporally dampens the neuropathic phenotype. However, the ensuing activation of a LCcontra→DRtcontrafacilitatory pain projection contributes to chronic pain, whereas global bilateral LC activation contributes to associated depressive-like phenotype