Interplay between subthalamic nucleus and spinal cord controls parkinsonian nociceptive disorders.

BACKGROUND: Pain is a non-motor symptom that impairs quality of life in Parkinson's patients. Pathological nociceptive hypersensitivity in patients could be due to changes in the processing of somatosensory information at the level of the basal ganglia, including the subthalamic nucleus (STN), but the underlying mechanisms are not yet defined. Here, we investigated the interaction between the STN and the dorsal horn of the spinal cord (DHSC), by first examining the nature of STN neurons that respond to peripheral nociceptive stimulation and the nature of their responses under normal and pathological conditions. Next, we studied the consequences of deep brain stimulation (DBS) of the STN on the electrical activity of DHSC neurons. Then, we investigated whether the therapeutic effect of STN-DBS would be mediated by the brainstem descending pathway involving the rostral ventromedial medulla (RVM). Finally, to better understand how the STN modulates allodynia, we used Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) expressed in the STN. METHODS: The study was carried out on the 6-OHDA rodent model of Parkinson's disease, obtained by stereotactic injection of the neurotoxin into the medial forebrain bundle of rats and mice. In these animals, we used motor and nociceptive behavioral tests, in vivo electrophysiology of STN and wide dynamic range (WDR) DHSC neurons in response to peripheral stimulation, deep brain stimulation of the STN and the selective DREADD approach. Vglut2-ires-cre mice were used to specifically target and inhibit STN glutamatergic neurons. RESULTS: STN neurons are able to detect nociceptive stimuli, encode their intensity and generate windup-like plasticity, like WDR neurons in the DHSC. These phenomena are impaired in dopamine-depleted animals, as the intensity response is altered in both spinal and subthalamic neurons. Furthermore, As with L-Dopa, STN-DBS in rats ameliorated 6-OHDA-induced allodynia, and this effect is mediated by descending brainstem projections leading to normalization of nociceptive integration in DHSC neurons. Furthermore, this therapeutic effect was reproduced by selective inhibition of STN glutamatergic neurons in Vglut2-ires-cre mice. CONCLUSION: Our study highlights the centrality of the STN in nociceptive circuits, its interaction with the DHSC and its key involvement in pain sensation in Parkinson's disease. Furthermore, our results provide for the first-time evidence that subthalamic DBS produces analgesia by normalizing the responses of spinal WDR neurons via descending brainstem pathways. These effects are due to direct inhibition, rather than activation of glutamatergic neurons in the STN or passage fibers, as shown in the DREADDs experiment.

Pain hypersensitivity in a pharmacological mouse model of attention-deficit/hyperactivity disorder.

Clinical evidence suggests that pain hypersensitivity develops in patients with attention-deficit/hyperactivity disorder (ADHD). However, the mechanisms and neural circuits involved in these interactions remain unknown because of the paucity of studies in animal models. We previously validated a mouse model of ADHD obtained by neonatal 6-hydroxydopamine (6-OHDA) injection. Here, we have demonstrated that 6-OHDA mice exhibit a marked sensitization to thermal and mechanical stimuli, suggesting that phenotypes associated with ADHD include increased nociception. Moreover, sensitization to pathological inflammatory stimulus is amplified in 6-OHDA mice as compared to shams. In this ADHD model, spinal dorsal horn neuron hyperexcitability was observed. Furthermore, ADHD-related hyperactivity and anxiety, but not inattention and impulsivity, are worsened in persistent inflammatory conditions. By combining in vivo electrophysiology, optogenetics, and behavioral analyses, we demonstrated that anterior cingulate cortex (ACC) hyperactivity alters the ACC-posterior insula circuit and triggers changes in spinal networks that underlie nociceptive sensitization. Altogether, our results point to shared mechanisms underlying the comorbidity between ADHD and nociceptive sensitization. This interaction reinforces nociceptive sensitization and hyperactivity, suggesting that overlapping ACC circuits may be targeted to develop better treatments.

Dopaminergic neuromodulation of prefrontal cortex activity requires the NMDA receptor coagonist d-serine.

Prefrontal control of cognitive functions critically depends upon glutamatergic transmission and N-methyl D-aspartate (NMDA) receptors, the activity of which is regulated by dopamine. Yet whether the NMDA receptor coagonist d-serine is implicated in the dopamine-glutamate dialogue in the prefrontal cortex (PFC) and other brain areas remains unexplored. Here, using electrophysiological recordings, we show that d-serine is required for the fine-tuning of glutamatergic neurotransmission, neuronal excitability, and synaptic plasticity in the PFC through the actions of dopamine at D1 and D3 receptors. Using in vivo microdialysis, we show that D1 and D3 receptors exert a respective facilitatory and inhibitory influence on extracellular levels and activity of d-serine in the PFC, with actions expressed primarily via the cAMP/protein kinase A (PKA) signaling cascade. Further, using functional magnetic resonance imaging (fMRI) and behavioral assessment, we show that d-serine is required for the potentiation of cognition by D3R blockade as revealed in a test of novel object recognition memory. Collectively, these results unveil a key role for d-serine in the dopaminergic neuromodulation of glutamatergic transmission and PFC activity, findings with clear relevance to the pathogenesis and treatment of diverse brain disorders involving alterations in dopamine-glutamate cross-talk.

Do arthropods feel anxious during molts?

The molting process of arthropods, chiefly controlled by ecdysteroids, is generally considered very stressful. Our previous investigations have shown that crayfish, after having experienced stressful situations, display anxiety-like behavior (ALB), characterized by aversion to light in a dark/light plus-maze (DLPM). In the present experiments, the spontaneous exploratory behavior of isolated crayfish was analyzed in a DLPM at different stages of their molt cycle. All tested animals displayed transitory aversion to light similar to ALB, before and, mostly, after molting, but not during inter-molt. Injection of ecdysteroids into inter-molt animals elicited ALB after a delay of 4 days, suggesting a long-term, possibly indirect, hormonal effect. Importantly, ecdysteroid-induced ALB was suppressed by the injection of an anxiolytic benzodiazepine. Thus, molts and their hormonal control impose internal stress on crayfish, leading to aversion behavior that has the main characteristics of anxiety. These observations are possibly generalizable to many other arthropods.

Windup of Nociceptive Flexion Reflex Depends on Synaptic and Intrinsic Properties of Dorsal Horn Neurons in Adult Rats.

Windup, a progressive increase in spinal response to repetitive stimulations of nociceptive peripheral fibers, is a useful model to study central sensitization to pain. Windup is expressed by neurons in both the dorsal and ventral horn of the spinal cord. In juvenile rats, it has been demonstrated both in vivo and in vitro that windup depends on calcium-dependent intrinsic properties and their modulation by synaptic components. However, the involvement of these two components in the adults remains controversial. In the present study, by means of electromyographic and extracellular recordings, we show that windup in adults, in vivo, depends on a synaptic balance between excitatory N-methyl-D-aspartate (NMDA) receptors and inhibitory glycinergic receptors. We also demonstrate the involvement of L-type calcium channels in both the dorsal and ventral horn of the spinal cord. These results indicate that windup in adults is similar to juvenile rats and that windup properties are the same regardless of the spinal network, i.e., sensory or motor.

Alteration of nociceptive integration in the spinal cord of a rat model of Parkinson's disease.

BACKGROUND: Pain is a major non motor symptom that contributes to impaired quality of life in PD. However, its mechanism is unknown. OBJECTIVES AND METHODS: We sought to identify the pain phenotypes and parallel changes in spinal integration of peripheral stimuli in a rat model of PD induced by lesions of SN dopamine neurons, using behavioral plantar and von Frey tests as well as electrophysiology of the dorsal horn. RESULTS: We show that dopamine depletion by 6-OHDA induced hypersensitivity to mechanical and thermal stimuli. These abnormal behaviors were paralleled by increased neuronal responses and hyperexcitability of wide dynamic range neurons of lamina V of the dorsal horn of the spinal cord in response to electrical stimulation of the sciatic nerve in the 6-OHDA model as compared to sham rats. CONCLUSIONS: These results provide evidence for alteration of nociceptive integration in the spinal dorsal horn neurons in 6-OHDA rats that can reflect changes in pain behavior. © 2018 International Parkinson and Movement Disorder Society.

Alteration of size perception: serotonin has opposite effects on the aggressiveness of crayfish confronting either a smaller or a larger rival.

We injected serotonin (5-HT) into adult male crayfish before pairing them with size-matched non-injected competitors, and observed dyadic agonistic interactions. Paradoxically, 5-HT elicited opposite behavioral responses if the injected animal was opposed by a smaller or larger rival: the level of aggressiveness of the injected crayfish was higher when facing a larger rival but lower when facing a smaller rival. Our results indicate that the effects of 5-HT on aggressiveness are dependent on the perception of the relative size difference of the opponent. In both cases, however, 5-HT significantly delayed the decision to retreat. We conclude that 5-HT does not primarily act on aggressiveness but rather on the brain centers that integrate risk assessment and/or decision making, which then modulate the aggressive response. Our findings support a reinterpretation of the role of 5-HT in crustacean agonistic behavior that may be of interest for studies of other animals.

Group I metabotropic glutamate receptor plasticity after peripheral inflammation alters nociceptive transmission in the dorsal of the spinal cord in adult rats.

Abstract: The dorsal horn of the spinal cord is a crucial site for pain transmission and modulation. Dorsal horn neurons of the spinal cord express group I metabotropic glutamate receptors (group I mGluRs) that exert a complex role in nociceptive transmission. In particular, group I mGluRs promote the activation of L-type calcium channels, voltage-gated channels involved in short- and long-term sensitization to pain. In this study, we analyzed the role of group I mGluRs in spinal nociceptive transmission and the possible cooperation between these receptors and L-type calcium channels in the pathophysiology of pain transmission in the dorsal horn of the spinal cord. We demonstrate that the activation of group I mGluRs induces allodynia and L-type calcium channel-dependent increase in nociceptive field potentials following sciatic nerve stimulation. Surprisingly, in a model of persistent inflammation induced by complete Freund's adjuvant, the activation of group I mGluRs induced an analgesia and a decrease in nociceptive field potentials. Among the group I mGluRs, mGluR1 promotes the activation of L-type calcium channels and increased nociceptive transmission while mGluR5 induces the opposite through the inhibitory network. These results suggest a functional switch exists in pathological conditions that can change the action of group I mGluR agonists into possible analgesic molecules, thereby suggesting new therapeutic perspectives to treat persistent pain in inflammatory settings.

Cav1.2 and Cav1.3 L-type calcium channels independently control short- and long-term sensitization to pain.

KEY POINTS: L-type calcium channels in the CNS exist as two subunit forming channels, Cav1.2 and Cav1.3, which are involved in short- and long-term plasticity. We demonstrate that Cav1.3 but not Cav1.2 is essential for wind-up. These results identify Cav1.3 as a key conductance responsible for short-term sensitization in physiological pain transmission. We confirm the role of Cav1.2 in a model of long-term plasticity associated with neuropathic pain. Up-regulation of Cav1.2 and down-regultation of Cav1.3 in neuropathic pain underlies the switch from physiology to pathology. Finally, the results of the present study reveal that therapeutic targeting molecular pathways involved in wind-up may be not relevant in the treatment of neuropathy. ABSTRACT: Short-term central sensitization to pain temporarily increases the responsiveness of nociceptive pathways after peripheral injury. In dorsal horn neurons (DHNs), short-term sensitization can be monitored through the study of wind-up. Wind-up, a progressive increase in DHNs response following repetitive peripheral stimulations, depends on the post-synaptic L-type calcium channels. In the dorsal horn of the spinal cord, two L-type calcium channels are present, Cav1.2 and Cav1.3, each displaying specific kinetics and spatial distribution. In the present study, we used a mathematical model of DHNs in which we integrated the specific patterns of expression of each Cav subunits. This mathematical approach reveals that Cav1.3 is necessary for the onset of wind-up, whereas Cav1.2 is not and that synaptically triggered wind-up requires NMDA receptor activation. We then switched to a biological preparation in which we knocked down Cav subunits and confirmed the prominent role of Cav1.3 in both naive and spinal nerve ligation model of neuropathy (SNL). Interestingly, although a clear mechanical allodynia dependent on Cav1.2 expression was observed after SNL, the amplitude of wind-up was decreased. These results were confirmed with our model when adapting Cav1.3 conductance to the changes observed after SNL. Finally, our mathematical approach predicts that, although wind-up amplitude is decreased in SNL, plateau potentials are not altered, suggesting that plateau and wind-up are not fully equivalent. Wind-up and long-term hyperexcitability of DHNs are differentially controlled by Cav1.2 and Cav1.3, therefore confirming that short- and long-term sensitization are two different phenomena triggered by distinct mechanisms.

Impairment of GABAB receptor dimer by endogenous 14-3-3ζ in chronic pain conditions.

In the central nervous system, the inhibitory GABAB receptor is the archetype of heterodimeric G protein-coupled receptors (GPCRs). However, the regulation of GABAB dimerization, and more generally of GPCR oligomerization, remains largely unknown. We propose a novel mechanism for inhibition of GPCR activity through de-dimerization in pathological conditions. We show here that 14-3-3ζ, a GABAB1-binding protein, dissociates the GABAB heterodimer, resulting in the impairment of GABAB signalling in spinal neurons. In the dorsal spinal cord of neuropathic rats, 14-3-3ζ is overexpressed and weakens GABAB inhibition. Using anti-14-3-3ζ siRNA or competing peptides disrupts 14-3-3ζ/GABAB1 interaction and restores functional GABAB heterodimers in the dorsal horn. Importantly, both strategies greatly enhance the anti-nociceptive effect of intrathecal Baclofen in neuropathic rats. Taken together, our data provide the first example of endogenous regulation of a GPCR oligomeric state and demonstrate its functional impact on the pathophysiological process of neuropathic pain sensitization.

Serotonin, but not dopamine, controls the stress response and anxiety-like behavior in the crayfish Procambarus clarkii.

In the animal kingdom, biogenic amines are widespread modulators of the nervous system that frequently interact to control mood. Our previous investigations in crayfish (Procambarus clarkii) have established that stress induces changes in brain serotonin (5-HT) concentrations that are responsible for the appearance of anxiety-like behavior (ALB). Here, we further analyze the roles of 5-HT and another biogenic amine, dopamine (DA), on the crayfish response to stress. We show that the intensity of crayfish ALB depends on the intensity of stressful stimulation and is associated with increased concentrations of 5-HT in the brain. These 5-HT levels were significantly correlated, before, as well as after stress, with those of DA, which were approximately 3- to 5-times less abundant. However, whereas the degree of ALB was clearly correlated with brain 5-HT concentrations, it was not significantly correlated with DA. Moreover, in contrast to injections of 5-HT, DA injections were not able to elicit a stress response or ALB. In addition, 5-HT and DA levels were not modified by treatment with the anxiolytic chlordiazepoxide, confirming that suppression of ALB by this GABA-A receptor ligand acts downstream and is independent of changes in crayfish bioamine levels. Our study also provides evidence that the anxiogenic effect of 5-HT injections can be prevented by a preliminary injection of 5-HT antagonists. Altogether, our results emphasize that the rises in brain concentrations of 5-HT, but not DA, play a role in controlling the induction and the intensity of crayfish ALB.

Extracellular signal-regulated kinase phosphorylation in forebrain neurones contributes to osmoregulatory mechanisms.

Vasopressin secretion from the magnocellular neurosecretory cells (MNCs) is crucial for body fluid homeostasis. Osmotic regulation of MNC activity involves the concerted modulation of intrinsic mechanosensitive ion channels, taurine release from local astrocytes as well as excitatory inputs derived from osmosensitive forebrain regions. Extracellular signal-regulated protein kinases (ERK) are mitogen-activated protein kinases that transduce extracellular stimuli into intracellular post-translational and transcriptional responses, leading to changes in intrinsic neuronal properties and synaptic function. Here, we investigated whether ERK activation (i.e. phosphorylation) plays a role in the functioning of forebrain osmoregulatory networks. We found that within 10 min after intraperitoneal injections of hypertonic saline (3 m, 6 m) in rats, many phosphoERK-immunopositive neurones were observed in osmosensitive forebrain regions, including the MNC containing supraoptic nuclei. The intensity of ERK labelling was dose-dependent. Reciprocally, slow intragastric infusions of water that lower osmolality reduced basal ERK phosphorylation. In the supraoptic nucleus, ERK phosphorylation predominated in vasopressin neurones vs. oxytocin neurones and was absent from astrocytes. Western blot experiments confirmed that phosphoERK expression in the supraoptic nucleus was dose dependent. Intracerebroventricular administration of the ERK phosphorylation inhibitor U 0126 before a hyperosmotic challenge reduced the number of both phosphoERK-immunopositive neurones and Fos expressing neurones in osmosensitive forebrain regions. Blockade of ERK phosphorylation also reduced hypertonically induced depolarization and an increase in firing of the supraoptic MNCs recorded in vitro. It finally reduced hypertonically induced vasopressin release in the bloodstream. Altogether, these findings identify ERK phosphorylation as a new element contributing to the osmoregulatory mechanisms of vasopressin release.

Modulating Neural Circuits of Pain in Preclinical Models: Recent Insights for Future Therapeutics.

Chronic pain is a pathological state defined as daily pain sensation over three consecutive months. It affects up to 30% of the general population. Although significant research efforts have been made in the past 30 years, only a few and relatively low effective molecules have emerged to treat chronic pain, with a considerable translational failure rate. Most preclinical models have focused on sensory neurotransmission, with particular emphasis on the dorsal horn of the spinal cord as the first relay of nociceptive information. Beyond impaired nociceptive transmission, chronic pain is also accompanied by numerous comorbidities, such as anxiety-depressive disorders, anhedonia and motor and cognitive deficits gathered under the term "pain matrix". The emergence of cutting-edge techniques assessing specific neuronal circuits allow in-depth studies of the connections between "pain matrix" circuits and behavioural outputs. Pain behaviours are assessed not only by reflex-induced responses but also by various or more complex behaviours in order to obtain the most complete picture of an animal's pain state. This review summarises the latest findings on pain modulation by brain component of the pain matrix and proposes new opportunities to unravel the mechanisms of chronic pain.

Control of motor activity in crayfish by the steroid hormone 20-hydroxyecdysone via motoneuron excitability and sensory-motor integration.

We studied the effects of the molting hormone 20-hydroxyecdysone (20E) on leg sensory-motor networks of the red swamp crayfish, Procambarus clarkii. The hormone was injected in isolated crayfish and network activity was analyzed 3 days after injection using electrophysiology on an in vitro preparation of the leg locomotor network. This 20E treatment deeply reduced motor activity, by affecting both intrinsic motoneuron (MN) properties and sensory-motor integration. Indeed, we noticed a general decrease in motor nerve tonic activities, principally in depressor and promotor nerves. Moreover, intracellular recordings of depressor MNs confirmed a decrease of MN excitability due to a drop in input resistance. In parallel, sensory inputs originating from a proprioceptor, which codes joint movements controlled by these MNs, were also reduced. The shape of excitatory post-synaptic potentials (PSPs) triggered in MNs by sensory activity of this proprioceptor showed a reduction of polysynaptic components, whereas inhibitory PSPs were suppressed, demonstrating that 20E acted also on interneurons relaying sensory to motor inputs. Consequently, 20E injection modified the whole sensory-motor loop, as demonstrated by the alteration of the resistance reflex amplitude. These locomotor network changes induced by 20E were consistent with the decrease of locomotion observed in a behavioral test. In summary, 20E controls locomotion during crayfish premolt by acting on both MN excitability and sensory-motor integration. Among these cooperative effects, the drop of input resistance of MNs seems to be mostly responsible for the reduction of motor activity.

Glial D-serine gates NMDA receptors at excitatory synapses in prefrontal cortex.

N-methyl-D-aspartate receptors (NMDARs) subserve numerous neurophysiological and neuropathological processes in the cerebral cortex. Their activation requires the binding of glutamate and also of a coagonist. Whereas glycine and D-serine (D-ser) are candidates for such a role at central synapses, the nature of the coagonist in cerebral cortex remains unknown. We first show that the glycine-binding site of NMDARs is not saturated in acute slices preparations of medial prefrontal cortex (mPFC). Using enzymes that selectively degrade either D-ser or glycine, we demonstrate that under the present conditions, D-ser is the principle endogenous coagonist of synaptic NMDARs at mature excitatory synapses in layers V/VI of mPFC where it is essential for long-term potentiation (LTP) induction. Furthermore, blocking the activity of glia with the metabolic inhibitor, fluoroacetate, impairs NMDAR-mediated synaptic transmission and prevents LTP induction by reducing the extracellular levels of D-serine. Such deficits can be restored by exogenous D-ser, indicating that the D-amino acid mainly originates from glia in the mPFC, as further confirmed by double-immunostaining studies for D-ser and anti-glial fibrillary acidic protein. Our findings suggest that D-ser modulates neuronal networks in the cerebral cortex by gating the activity of NMDARs and that altering its levels is relevant to the induction and potentially treatment of psychiatric and neurological disorders.

Microglial P2X4 receptors are essential for spinal neurons hyperexcitability and tactile allodynia in male and female neuropathic mice.

In neuropathic pain, recent evidence has highlighted a sex-dependent role of the P2X4 receptor in spinal microglia in the development of tactile allodynia following nerve injury. Here, using internalization-defective P2X4mCherryIN knockin mice (P2X4KI), we demonstrate that increased cell surface expression of P2X4 induces hypersensitivity to mechanical stimulations and hyperexcitability in spinal cord neurons of both male and female naive mice. During neuropathy, both wild-type (WT) and P2X4KI mice of both sexes develop tactile allodynia accompanied by spinal neuron hyperexcitability. These responses are selectively associated with P2X4, as they are absent in global P2X4KO or myeloid-specific P2X4KO mice. We show that P2X4 is de novo expressed in reactive microglia in neuropathic WT and P2X4KI mice of both sexes and that tactile allodynia is relieved by pharmacological blockade of P2X4 or TrkB. These results show that the upregulation of P2X4 in microglia is crucial for neuropathic pain, regardless of sex.

A photoswitchable inhibitor of TREK channels controls pain in wild-type intact freely moving animals.

By endowing light control of neuronal activity, optogenetics and photopharmacology are powerful methods notably used to probe the transmission of pain signals. However, costs, animal handling and ethical issues have reduced their dissemination and routine use. Here we report LAKI (Light Activated K+ channel Inhibitor), a specific photoswitchable inhibitor of the pain-related two-pore-domain potassium TREK and TRESK channels. In the dark or ambient light, LAKI is inactive. However, alternating transdermal illumination at 365 nm and 480 nm reversibly blocks and unblocks TREK/TRESK current in nociceptors, enabling rapid control of pain and nociception in intact and freely moving mice and nematode. These results demonstrate, in vivo, the subcellular localization of TREK/TRESK at the nociceptor free nerve endings in which their acute inhibition is sufficient to induce pain, showing LAKI potential as a valuable tool for TREK/TRESK channel studies. More importantly, LAKI gives the ability to reversibly remote-control pain in a non-invasive and physiological manner in naive animals, which has utility in basic and translational pain research but also in in vivo analgesic drug screening and validation, without the need of genetic manipulations or viral infection.

The impact of C-tactile low-threshold mechanoreceptors on affective touch and social interactions in mice.

Affective touch is necessary for proper neurodevelopment and sociability. However, it remains unclear how the neurons innervating the skin detect affective and social behaviors. The C low-threshold mechanoreceptors (C-LTMRs), a specific population of somatosensory neurons in mice, appear particularly well suited, physiologically and anatomically, to perceive affective and social touch. However, their contribution to sociability has not been resolved yet. Our observations revealed that C-LTMR functional deficiency induced social isolation and reduced tactile interactions in adulthood. Conversely, transient increase in C-LTMR excitability in adults, using chemogenetics, was rewarding, promoted touch-seeking behaviors, and had prosocial influences on group dynamics. This work provides the first empirical evidence that specific peripheral inputs alone can drive complex social behaviors. It demonstrates the existence of a specialized neuronal circuit, originating in the skin, wired to promote interactions with other individuals.

Switch of serotonergic descending inhibition into facilitation by a spinal chloride imbalance in neuropathic pain.

Descending control from the brain to the spinal cord shapes our pain experience, ranging from powerful analgesia to extreme sensitivity. Increasing evidence from both preclinical and clinical studies points to an imbalance toward descending facilitation as a substrate of pathological pain, but the underlying mechanisms remain unknown. We used an optogenetic approach to manipulate serotonin (5-HT) neurons of the nucleus raphe magnus that project to the dorsal horn of the spinal cord. We found that 5-HT neurons exert an analgesic action in naïve mice that becomes proalgesic in an experimental model of neuropathic pain. We show that spinal KCC2 hypofunction turns this descending inhibitory control into paradoxical facilitation; KCC2 enhancers restored 5-HT-mediated descending inhibition and analgesia. Last, combining selective serotonin reuptake inhibitors (SSRIs) with a KCC2 enhancer yields effective analgesia against nerve injury-induced pain hypersensitivity. This uncovers a previously unidentified therapeutic path for SSRIs against neuropathic pain.

Glia-dependent switch of kainate receptor presynaptic action.

Presynaptic kainate receptors (KARs) exert a modulatory action on transmitter release. This effect can be switched from facilitation to inhibition by an increased concentration of KAR agonists. We here report that activation of presynaptic GluK1-containing KARs facilitates GABA release on oxytocin and vasopressin neurons in the supraoptic nucleus of the hypothalamus. Increase in ambient levels of glutamate associated with the physiological reduction of astrocytic coverage of oxytocin neurons in lactating rats switches this KAR-mediated facilitation to inhibition of GABAergic transmission. This effect was reproduced in both oxytocin and vasopressin neurons of virgin rats when glutamate transporters were blocked pharmacologically, thereby establishing that enhanced levels of extracellular glutamate induce the switch in KAR-mediated action. The facilitation of GABA release was inhibited with philanthotoxin, a Ca(2+)-permeable KAR antagonist, suggesting that this effect was associated with an ionotropic mode of action. Conversely, KAR-mediated inhibition was compromised in the presence of U73122, a phospholipase C inhibitor, in agreement with the involvement of a metabotropic pathway. We thus reveal that physiological astrocytic plasticity modifies the mode of action of presynaptic KARs, thereby inversing their coupling with GABA release.