Marie-José Freund-Mercier

GABA- and peptide-immunoreactivities co-localize in the rat central extended amygdala

THE central amygdaloid nucleus and the lateral bed nucleus of the stria terminalis are two similar telencephalic structures belonging to the central extended amygdala. These regions contain numerous peptidergic and GABAergic neurones which maintain the neurones projecting to the brain stem under tight intrinsic control. Using immunocytochemistry in colchicinetreated rats, we showed that, in the lateral subdivision of the central amygdaloid nucleus and in the dorsal part of the lateral bed nucleus of the stria terminalis, a population of GABAergic neurones is able to co-synthesize either corticotropin-releasing factor or methionineenkephalin, but never both peptides. These results suggest that, in the GABAergic intrinsic circuits of the central extended amygdala, co-liberated peptides can have a modulatory role on GABAergic actions.

A Time-Dependent History of Mood Disorders in a Murine Model of Neuropathic Pain

BACKGROUNDnChronic pain is clinically associated with the development of affective disorders. However, studies in animal models of neuropathic pain are contradictory and the relationship with mood disorders remains unclear. In this study, we aimed to characterize the affective consequences of neuropathic pain over time and to study potential underlying mechanisms.nnnMETHODSnNeuropathic pain was induced by inserting a polyethylene cuff around the main branch of the right sciatic nerve in C57BL/6J mice. Anxiety- and depression-related behaviors were assessed over 2 months, using a battery of tests, such as elevated plus maze, marble burying, novelty suppressed feeding, splash test, and forced swimming test. Plasma corticosterone levels were assessed by radioimmunoassay. We also investigated changes in cyclic adenosine monophosphate response element (CRE) activity using CRE-LacZ transgenic mice.nnnRESULTSnMice developed anxiety-related behavior 4 weeks after induction of the neuropathy, and depression-related behaviors were observed after 6 to 8 weeks. Control and neuropathic mice did not differ for basal or stress-induced levels of corticosterone or for hypothalamic-pituitary-adrenal axis negative feedback. After 8 weeks, the CRE-mediated activity decreased in the outer granule layer of dentate gyrus of neuropathic mice but not in the amygdala or in the anterior cingulate cortex.nnnCONCLUSIONSnOur results demonstrate that the affective consequences of neuropathic pain evolve over time, independently from the hypothalamic-pituitary-adrenal axis, which remains unaffected. CRE-mediated transcription within a limbic structure was altered at later time points of the neuropathy. These experiments provide a preclinical model to study time-dependent development of mood disorders and the underlying mechanism in a neuropathic pain context.

γ-Aminobutyric Acid Cells with Cocaine-Induced ΔFosB in the Ventral Tegmental Area Innervate Mesolimbic Neurons

BACKGROUNDnThe transcription factor DeltaFosB is implicated in the plasticity induced by drugs of abuse. We showed that psychostimulants induce DeltaFosB in gamma-aminobutyric acid (GABA) cells of a caudal subregion of the ventral tegmental area (VTA) that was named tail of the VTA (tVTA). Although tVTA mostly shares VTA inputs, its outputs remain to be characterized.nnnMETHODSnThe tVTA efferents were studied by iontophoretic injections of the anterograde tracer biotinylated dextran amine (BDA). To further study VTA inputs arising from tVTA, injections of the retrograde tracer Fluoro-Gold were combined with multiple labeling by immunohistochemistry in rats treated with cocaine. Indirect projections from the tVTA to the nucleus accumbens were assessed with a double-tracing approach, cholera toxin B subunit (CTB) being delivered in the nucleus accumbens and BDA in the tVTA.nnnRESULTSnTract-tracing studies showed that tVTA heavily projects to the midbrain dopaminergic system and revealed terminal appositions with dopamine cells in the VTA. Double-labeling studies demonstrated that this tVTA output is mostly GABAergic, includes cells in which cocaine exposure induces DeltaFosB, and displays appositions to dopamine cells projecting to the nucleus accumbens.nnnCONCLUSIONSnThe GABA neurons expressing DeltaFosB in the tVTA after cocaine exposure project to the dopamine mesolimbic neurons.

Differentiating Thermal Allodynia and Hyperalgesia Using Dynamic Hot and Cold Plate in Rodents

UNLABELLEDnIn animal studies, thermal sensitivity is mostly evaluated on the basis of nociceptive reaction latencies in response to a given thermal aversive stimulus. However, these techniques may be inappropriate to differentiate allodynia from hyperalgesia or to provide information differentiating the activation of nociceptor subtypes. The recent development of dynamic hot and cold plates, allowing computer-controlled ramps of temperature, may be useful for such measures. In this study, we characterized their interest for studying thermal nociception in freely moving mice and rats. We showed that escape behavior (jumps) was the most appropriate parameter in C57Bl/6J mice, whereas nociceptive response was estimated by using the sum of paw lickings and withdrawals in Sprague-Dawley rats. We then demonstrated that this procedure allows the detection of both thermal allodynia and hyperalgesia after peripheral pain sensitization with capsaicin in mice and in rats. In a condition of carrageenan-induced paw inflammation, we observed the previously described thermal hyperalgesia, but we also revealed that rats exhibit a clear thermal allodynia to a cold or a hot stimulus. These results demonstrate the interest of the dynamic hot and cold plate to study thermal nociception, and more particularly to study both thermal allodynia and hyperalgesia within a single paradigm in awake and freely moving rodents.nnnPERSPECTIVEnDespite its clinical relevance, thermal allodynia is rarely studied by researchers working on animal models. As shown after stimulation of capsaicin-sensitive fibers or during inflammatory pain, the dynamic hot and cold plate validated in the present study provides a useful tool to distinguish between thermal allodynia and thermal hyperalgesia in rodents.

Pharmacological recruitment of the GABAergic tail of the ventral tegmental area by acute drug exposure

BACKGROUND AND PURPOSE The tail of the ventral tegmental area (tVTA), also called the rostromedial tegmental nucleus, is a newly defined brain structure and a potential control centre for dopaminergic activity. It was identified by the induction of DeltaFosB following chronic cocaine exposure. In this work, we screened 20 drugs for their ability to induce FosB/DeltaFosB in the tVTA.

Chronic treatment with agonists of β2-adrenergic receptors in neuropathic pain

Expression of beta(2)-adrenoceptors (beta(2)-ARs) within the nociceptive system suggested their potential implication in nociception and pain. Recently, we demonstrated that these receptors are essential for neuropathic pain treatment by antidepressant drugs. The aim of the present study was to investigate whether the stimulation of beta(2)-ARs could in fact be adequate to alleviate neuropathic allodynia. Neuropathy was induced in mice by sciatic nerve cuffing. We demonstrate that chronic but not acute stimulation of beta(2)-ARs with agonists such as clenbuterol, formoterol, metaproterenol and procaterol suppressed neuropathic allodynia. By using a pharmacological approach with the beta(2)-AR antagonist ICI 118,551 or a transgenic approach with mice deficient for beta(2)-ARs, we confirmed that the antiallodynic effect of these agonists was specifically related to their action on beta(2)-ARs. We also showed that chronic treatment with the beta(1)-AR agonist xamoterol or with the beta(3)-AR agonist BRL 37344 had no effect on neuropathic allodynia. Chronic stimulation of beta(2)-ARs, but not beta(1)- or beta(3)-ARs, by specific agonists is thus able to alleviate neuropathic allodynia. This action of beta(2)-AR agonists might implicate the endogenous opioid system; indeed chronic clenbuterol effect can be acutely blocked by the delta-opioid receptor antagonist naltrindole. Present results show that beta(2)-ARs are not only essential for the antiallodynic action of antidepressant drugs on sustained neuropathic pain, but also that the stimulation of these receptors is sufficient to relieve neuropathic allodynia in a murine model. Our data suggest that beta(2)-AR agonists may potentially offer an alternative therapy to antidepressant drugs for the chronic treatment of neuropathic pain.

β2-Adrenoceptor agonists alleviate neuropathic allodynia in mice after chronic treatment

Background and purpose:u2002 Antidepressants are a first‐line treatment against neuropathic pain. We previously demonstrated that β2‐adrenoceptors are necessary for antidepressants to exert their anti‐allodynic action. The aim of the present study was to assess whether β2‐adrenoceptor agonists could be sufficient to alleviate neuropathic allodynia.

Control of the Nigrostriatal Dopamine Neuron Activity and Motor Function by the Tail of the Ventral Tegmental Area

Midbrain dopamine neurons are implicated in various psychiatric and neurological disorders. The GABAergic tail of the ventral tegmental area (tVTA), also named the rostromedial tegmental nucleus (RMTg), displays dense projections to the midbrain and exerts electrophysiological control over dopamine cells of the VTA. However, the influence of the tVTA on the nigrostriatal pathway, from the substantia nigra pars compacta (SNc) to the dorsal striatum, and on related functions remains to be addressed. The present study highlights the role played by the tVTA as a GABA brake for the nigrostriatal system, demonstrating a critical influence over motor functions. Using neuroanatomical approaches with tract tracing and electron microscopy, we reveal the presence of a tVTA–SNc–dorsal striatum pathway. Using in vivo electrophysiology, we prove that the tVTA is a major inhibitory control center for SNc dopamine cells. Using behavioral approaches, we demonstrate that the tVTA controls rotation behavior, motor coordination, and motor skill learning. The motor enhancements observed after ablation of the tVTA are in this regard comparable with the performance-enhancing properties of amphetamine, a drug used in doping. These findings demonstrate that the tVTA is a major GABA brake for nigral dopamine systems and nigrostriatal functions, and they raise important questions about how the tVTA is integrated within the basal ganglia circuitry. They also warrant further research on the tVTA’s role in motor and dopamine-related pathological contexts such as Parkinson’s disease.

Antidepressants suppress neuropathic pain by a peripheral β2-adrenoceptor mediated anti-TNFα mechanism.

Neuropathic pain is pain arising as a direct consequence of a lesion or disease affecting the somatosensory system. It is usually chronic and challenging to treat. Some antidepressants are first-line pharmacological treatments for neuropathic pain. The noradrenaline that is recruited by the action of the antidepressants on reuptake transporters has been proposed to act through β2-adrenoceptors (β2-ARs) to lead to the observed therapeutic effect. However, the complex downstream mechanism mediating this action remained to be identified. In this study, we demonstrate in a mouse model of neuropathic pain that an antidepressants effect on neuropathic allodynia involves the peripheral nervous system and the inhibition of cytokine tumor necrosis factor α (TNFα) production. The antiallodynic action of nortriptyline is indeed lost after peripheral sympathectomy, but not after lesion of central descending noradrenergic pathways. More particularly, we report that antidepressant-recruited noradrenaline acts, within dorsal root ganglia, on β2-ARs expressed by non-neuronal satellite cells. This stimulation of β2-ARs decreases the neuropathy-induced production of membrane-bound TNFα, resulting in relief of neuropathic allodynia. This indirect anti-TNFα action was observed with the tricyclic antidepressant nortriptyline, the selective serotonin and noradrenaline reuptake inhibitor venlafaxine and the β2-AR agonist terbutaline. Our data revealed an original therapeutic mechanism that may open novel research avenues for the management of painful peripheral neuropathies.

Nociceptive thresholds are controlled through spinal β2-subunit-containing nicotinic acetylcholine receptors.

Summary β2∗‐nAChRs are receptors essential for setting nociceptive thresholds by controlling GABAergic inhibition in the spinal cord. The participation of β2∗‐nAChRs in the modulation of nociceptive transmission suggest that these receptors might be targets of interest for developing selective pharmacological compounds in the context of pain treatment. ABSTRACT Although cholinergic drugs are known to modulate nociception, the role of endogenous acetylcholine in nociceptive processing remains unclear. In the current study, we evaluated the role of cholinergic transmission through spinal β2‐subunit‐containing nicotinic acetylcholine receptors in the control of nociceptive thresholds. We show that mechanical and thermal nociceptive thresholds are significantly lowered in β2∗‐knockout (KO) mice. Using nicotinic antagonists in these mice, we demonstrate that β2∗‐nAChRs are responsible for tonic inhibitory control of mechanical thresholds at the spinal level. We further hypothesized that tonic β2∗‐nAChR control of mechanical nociceptive thresholds might implicate GABAergic transmission since spinal nAChR stimulation can enhance inhibitory transmission. Indeed, the GABAA receptor antagonist bicuculline decreased the mechanical threshold in wild‐type but not β2∗‐KO mice, and the agonist muscimol restored basal mechanical threshold in β2∗‐KO mice. Thus, β2∗‐nAChRs appeared to be necessary for GABAergic control of nociceptive information. As a consequence of this defective inhibitory control, β2∗‐KO mice were also hyperresponsive to capsaicin‐induced C‐fiber stimulation. Our results indicate that β2∗‐nAChRs are implicated in the recruitment of inhibitory control of nociception, as shown by delayed recovery from capsaicin‐induced allodynia, potentiated nociceptive response to inflammation and neuropathy, and by the loss of high‐frequency transcutaneous electrical nerve stimulation (TENS)–induced analgesia in β2∗‐KO mice. As high‐frequency TENS induces analgesia through Aβ‐fiber recruitment, these data suggest that β2∗‐nAChRs may be critical for the gate control of nociceptive information by non‐nociceptive sensory inputs. In conclusion, acetylcholine signaling through β2∗‐nAChRs seems to be essential for setting nociceptive thresholds by controlling GABAergic inhibition in the spinal cord.