Involvement of Scratch2 in GalR1-mediated depression-like behaviors in the rat ventral periaqueductal gray.

Galanin receptor1 (GalR1) transcript levels are elevated in the rat ventral periaqueductal gray (vPAG) after chronic mild stress (CMS) and are related to depression-like behavior. To explore the mechanisms underlying the elevated GalR1 expression, we carried out molecular biological experiments in vitro and in animal behavioral experiments in vivo. It was found that a restricted upstream region of the GalR1 gene, from -250 to -220, harbors an E-box and plays a negative role in the GalR1 promoter activity. The transcription factor Scratch2 bound to the E-box to down-regulate GalR1 promoter activity and lower expression levels of the GalR1 gene. The expression of Scratch2 was significantly decreased in the vPAG of CMS rats. Importantly, local knockdown of Scratch2 in the vPAG caused elevated expression of GalR1 in the same region, as well as depression-like behaviors. RNAscope analysis revealed that GalR1 mRNA is expressed together with Scratch2 in both GABA and glutamate neurons. Taking these data together, our study further supports the involvement of GalR1 in mood control and suggests a role for Scratch2 as a regulator of depression-like behavior by repressing the GalR1 gene in the vPAG.

A Neural Circuit from Thalamic Paraventricular Nucleus to Central Amygdala for the Facilitation of Neuropathic Pain.

As one of the thalamic midline nuclei, the thalamic paraventricular nucleus (PVT) is considered to be an important signal integration site for many descending and ascending pathways that modulate a variety of behaviors, including feeding, emotions, and drug-seeking. A recent study has demonstrated that the PVT is implicated in the acute visceral pain response, but it is unclear whether the PVT plays a critical role in the central processing of chronic pain. Here, we report that the neurons in the posterior portion of the PVT (pPVT) and their downstream pathway are involved in descending nociceptive facilitation regarding the development of neuropathic pain conditions in male rats. Lesions or inhibition of pPVT neurons alleviated mechanical allodynia induced by spared nerve injury (SNI). The excitability of pPVT-central amygdala (CeA) projection neurons was significantly increased in SNI rats. Importantly, selective optogenetic activation of the pPVT-CeA pathway induced obvious mechanical hypersensitivity in naive rats. In addition, we used rabies virus (RV)-based and cell-type-specific retrograde transsynaptic tracing techniques to define a novel neuronal circuit in which glutamatergic neurons in the vlPAG were the target of the pPVT-CeA descending facilitation pathway. Our data suggest that this pPVTGlu+-CeA-vlPAGGlu+ circuit mediates central mechanisms of descending pain facilitation underlying persistent pain conditions.SIGNIFICANCE STATEMENT Studies have shown that the interactions between the posterior portion of the thalamic paraventricular nucleus (pPVT) and central amygdala (CeA) play a critical role in pain-related emotional regulation. However, most reports have associated this circuit with fear and anxiety behaviors. Here, an integrative approach of behavioral tests, electrophysiology, and immunohistochemistry was used to advance the novel concept that the pPVT-CeA pathway activation facilitates neuropathic pain processing. Using rabies virus (RV)-based and cell-type-specific retrograde transsynaptic tracing techniques, we found that glutamatergic neurons in the vlPAG were the target of the pPVT-CeA pathway. Thus, this study indicates the involvement of a pPVTGlu+-CeA-vlPAGGlu+ pathway in a descending facilitatory mechanism underlying neuropathic pain.

Secondary cluster headache due to a contralateral demyelinating periaqueductal gray matter lesion.

OBJECTIVES/BACKGROUND: Tension-type headache and migraine without aura are the most common primary headaches occurring in people with demyelinating diseases, whereas cluster headache (CH) can be considered exceptional. The location of demyelinating lesions could be strategic in these cases, involving areas interacting with the trigeminovascular system. METHODS AND RESULTS: We report a case of a 54-year-old woman with right-sided CH as the initial manifestation of multiple sclerosis and showing a left dorsal brainstem lesion on magnetic resonance imaging, in the region of the dorsal longitudinal fasciculus (DLF). CONCLUSION: Our case seems to suggest a possible role of the DLF in the process that leads to CH attacks. Because neuroimaging clearly showed a lesion contralateral to CH pain, we hypothesize that some fibers from periaqueductal gray matter project to the contralateral side, besides the known ipsilateral connections.

Deficits in ascending and descending pain modulation pathways in patients with postherpetic neuralgia.

Postherpetic Neuralgia (PHN), develops after the resolution of the herpes zoster mucocutaneous eruption, is a debilitating chronic pain. However, there is a lack of knowledge regarding the underlying mechanisms associated with ascending and descending pain modulations in PHN patients. Here, we combined psychophysics with structural and functional magnetic resonance imaging (MRI) techniques to investigate the brain alternations in PHN patients. Psychophysical tests showed that compared with healthy controls, PHN patients had increased state and trait anxiety and depression. Structural MRI data indicated that PHN patients had significantly smaller gray matter volumes of the thalamus and amygdala than healthy controls, and the thalamus volume was negatively correlated with pain intensity (assessed using the Short-form of the McGill pain questionnaire) in PHN patients. When the thalamus and periaqueductal gray matter (PAG) were used as the seeds, resting-state functional MRI data revealed abnormal patterns of functional connectivity within ascending and descending pain pathways in PHN patients, e.g., increased functional connectivity between the thalamus and somatosensory cortices and decreased functional connectivity between the PAG and frontal cortices. In addition, subjective ratings of both Present Pain Index (PPI) and Beck-Depression Inventory (BDI) were negatively correlated with the strength of functional connectivity between the PAG and primary somatosensory cortex (SI), and importantly, the effect of BDI on PPI was mediated by the PAG-SI functional connectivity. Overall, our results provided evidence suggesting deficits in ascending and descending pain modulation pathways, which were highly associated with the intensity of chronic pain and its emotional comorbidities in PHN patients. Therefore, our study deepened our understanding of the pathogenesis of PHN, which would be helpful in determining the optimized treatment for the patients.

Astrocyte activation in the periaqueductal gray promotes descending facilitation to cancer-induced bone pain through the JNK MAPK signaling pathway.

Descending nociceptive modulation from the supraspinal structures has an important role in cancer-induced bone pain (CIBP). Midbrain ventrolateral periaqueductal gray (vlPAG) is a critical component of descending nociceptive circuits; nevertheless, its precise cellular and molecular mechanisms involved in descending facilitation remain elusive. Our previous study has shown that the activation of p38 MAPK in vlPAG microglia is essential for the neuropathic pain sensitization. However, the existence of potential connection between astrocytes and c-Jun N-terminal kinase (JNK) pathway in CIBP has not yet been elucidated. The following study examines the involvement of astrocyte activation and upregulation of p-JNK in vlPAG, using a CIBP rat model. Briefly, CIBP was mimicked by an intramedullary injection of Walker 256 mammary gland carcinoma cells into the animal tibia. A significant increase in expression levels of astrocytes in the vlPAG of CIBP rats was observed. Furthermore, stereotaxic microinjection of the astrocytic cytotoxin L-α-aminoadipic acid decreased the mechanical allodynia as well as established and reversed the astrocyte activation in CIBP rats. A significant increase in expression levels of p-JNK in astrocytes in vlPAG of CIBP rats was also observed. Moreover, the intrathecal administration of JNK inhibitors SP600125 reduced the expression of glial fibrillary acidic protein, while microinjection of the SP600125 decreased the mechanical allodynia of CIBP rats. These results suggested that CIBP is associated with astrocyte activation in the vlPAG that probably participates in driving descending pain facilitation through the JNK MAPK signaling pathway. To sum up, these findings reveal a novel site of astrocytes modulation of CIBP.

Region-specific deletions of the glutamate transporter GLT1 differentially affect nerve injury-induced neuropathic pain in mice.

Glutamate is a major excitatory neurotransmitter and plays an important role in neuropathic pain, which is frequently caused by nerve damage. According to recent studies, nerve injury induces changes in glutamatergic transmission in the spinal cord and several supraspinal regions, including the periaqueductal gray (PAG). Among glutamate signaling components, accumulating evidence suggests that the glial glutamate transporter GLT1 plays a critical role in neuropathic pain. Indeed, GLT1 expression is reduced in the spinal cord but increased in the PAG after nerve injury, suggesting that the role of GLT1 in neuropathic pain may vary according to the brain region. In this study, we generated PAG-specific and spinal cord-specific GLT1 knockout mice. Nerve injury-induced neuropathic pain was enhanced in spinal cord-specific GLT1 knockout mice but alleviated in PAG-specific GLT1 knockout mice. Thus, nerve injury may enhance glutamatergic neurotransmission from primary sensory neurons to the post-synaptic dorsal horn following downregulation of GLT1 in the spinal cord and result in inadequate descending pain inhibition caused by GLT1 upregulation in the PAG, resulting in neuropathic pain. In addition, ceftriaxone upregulated GLT1 expression in the spinal cord, but not the PAG, of control mice and attenuated tactile hypersensitivity in nerve-injured control mice but not in nerve-injured spinal cord-specific GLT1 knockout mice. Based on these results, the anti-neuropathic pain effect of ceftriaxone is mediated by the upregulation of GLT1 expression in the spinal cord. Thus, selective upregulation of spinal GLT1 and/or downregulation of GLT1 in the PAG represents a potentially novel strategy for the treatment of neuropathic pain.

Participation of pro-inflammatory cytokines in neuropathic pain evoked by chemotherapeutic oxaliplatin via central GABAergic pathway.

Background Neuropathic pain is observed in patients as chemotherapeutic oxaliplatin is used to treat metastatic digestive tumors; however, the mechanisms responsible for hyperalgesia are not well understood. Chronic neuroinflammation is one of the hallmarks of pathophysiology of neuropathic pain. Since the midbrain periaqueductal gray is an important component of the descending inhibitory pathway controlling on central pain transmission, we examined the role for pro-inflammatory cytokines system of the periaqueductal gray in regulating mechanical hyperalgesia and cold hypersensitivity evoked by oxaliplatin. Methods Neuropathic pain was induced by intraperitoneal injection of oxaliplatin in rats. ELISA and western blot analysis were used to examine pro-inflammatory cytokine levels and their receptors expression. Results IL-1ß, IL-6, and TNF-α were elevated within the periaqueductal gray of oxaliplatin rats. Protein expression of IL-1ß, IL-6, and TNF-α receptors (namely, IL-1R, IL-6R, and TNFR subtype TNFR1) in the plasma membrane periaqueductal gray of oxaliplatin rats was upregulated, whereas the total expression of pro-inflammatory cytokine receptors was not altered. In oxaliplatin rats, impaired inhibitory gamma-aminobutyric acid within the periaqueductal gray was accompanied with decreases in withdrawal thresholds to mechanical stimulus and % time spent on the cold plate. Our data further showed that the concentrations of gamma-aminobutyric acid were largely restored by blocking those pro-inflammatory cytokine receptors in periaqueductal gray of oxaliplatin rats; and mechanical hyperalgesia and cold hypersensitivity evoked by oxaliplatin were attenuated. Stimulation of gamma-aminobutyric acid receptors in the periaqueductal gray also blunted neuropathic pain in oxaliplatin rats. Conclusions Our data suggest that the upregulation of pro-inflammatory cytokines and membrane pro-inflammatory cytokine receptor in the periaqueductal gray of oxaliplatin rats is likely to impair the descending inhibitory pathways in regulating pain transmission and thereby contributes to the development of neuropathic pain after application of chemotherapeutic oxaliplatin.

In vivo structural imaging in rats reveals neuroanatomical correlates of behavioral sub-dimensions of cocaine addiction.

Cocaine addiction is a multi-dimensional behavioral disorder characterized by a loss of control over cocaine taking despite of detrimental consequences. Structural MRI studies have revealed association between cocaine consumption and gray matter volume (GMV) in cocaine-addicted patients. However, the behavioral correlates of GMV in cocaine addiction are poorly understood. Here, we used a DSM-IV-based rat model of cocaine addiction with high face validity for structural imaging. According to three behavioral sub-dimensions of addiction, rats were separated into two groups showing either addict-like or non-addict-like behavior. These behavioral sub-dimensions were (1) the inability to refrain from drug-seeking and taking, (2) high motivation for the drug, and (3) maintained drug use despite negative consequences. In these rats, we performed structural MRI with voxel-based morphometry and analyzed the interaction of GMV with behavioral sub-dimensions in cocaine-addicted rats. Our major findings are that GMV differentially correlate with the inability to refrain from drug-seeking and taking in addict-like and non-addict-like rats within the somatosensory cortices and the amygdala. High motivation for the drug differentially correlates with GMV in addict-like and non-addict-like rats within the medial prefrontal cortex, and maintained drug use despite negative consequences differentially correlates with GMV in these two groups of rats within the periaqueductal gray. Our results demonstrate that the behavioral differences characterizing addict-like and non-addict-like rats in each behavioral sub-dimension of addiction are reflected by divergent covariance with GMV. We conclude that structural imaging provides specific neuroanatomical correlates of behavioral sub-dimensions of addiction.

Glial activation in the periaqueductal gray promotes descending facilitation of neuropathic pain through the p38 MAPK signaling pathway.

The midbrain ventrolateral periaqueductal gray (VL-PAG) is a key component that mediates pain modulation. Although spinal cord glial cells appear to play an important role in chronic pain development, the precise mechanisms involving descending facilitation pathways from the PAG following nerve injury are poorly understood. This study shows that cellular events that occur during glial activation in the VL-PAG may promote descending facilitation from the PAG during neuropathic pain. Chronic constriction nerve injury (CCI) was induced by ligature construction of the sciatic nerve in male Sprague-Dawley rats. Behavioral responses to noxious mechanical (paw withdrawal threshold; PWT) and thermal (paw withdrawal latency; PWL) stimuli were evaluated. After CCI, immunohistochemical and Western blot analysis of microglia and astrocytes in the VL-PAG showed morphological and quantitative changes indicative of activation in microglia and astrocytes. Intra-VL-PAG injection of microglial or astrocytic inhibitors attenuated PWT and PWL at days 7 and 14, respectively, following CCI. We also evaluated the effects of intra-VL-PAG administration of the phosphorylated p38 mitogen-activated protein kinase (p-p38 MAPK) inhibitor SB 203580 at day 7 after CCI. This treatment abolished microglial activation and produced a significant time-dependent attenuation of PWT and PWL. Western blot analysis showed localized expression of p-p38 in the VL-PAG after CCI. P-p38 was expressed in labeled microglia of the VL-PAG but was not present in astrocytes and neurons on day 7 after CCI. These results demonstrate that CCI-induced neuropathic pain is associated with glial activation in the VL-PAG, which likely participates in descending pain facilitation through the p38 MAPK signaling pathway.

[An update on the conceptual and classification issues of anxiety, its neuroanatomy and problems of anxiolytic drug discovery]. / A szorongás konceptuális aspektusai, klasszifikációja, neuroanatómiája és az anxiolítikum-fejlesztés problémái.

Anxiety disorders are highly prevalent psychiatric diseases. In this short review we provide an overview of concepts of fear, anxiety and anxiety disorders. In addition, based on the recent literature, neuroanatomical structures involved in anxiety and functional/structural changes of these structures in anxiety disorders are also discussed. Furthemore, the pitfalls of anxiolytic drug discovery is also concerned in the paper.

Hypofunction of glutamatergic neurotransmission in the periaqueductal gray contributes to nerve-injury-induced neuropathic pain.

Neuropathic pain, a chronic pain due to neuronal lesion, remains unaltered even after the injury-induced spinal afferent discharges have declined, suggesting an involvement of supraspinal dysfunction. The midbrain ventrolateral periaqueductal gray (vlPAG) is known to be a crucial supraspinal region for initiating descending pain inhibition, but its role in neuropathic pain remains unclear. Therefore, here we examined neuroplastic changes in the vlPAG of midbrain slices isolated from neuropathic rats induced by L5/L6 spinal nerve ligation (SNL) via electrophysiological and neurochemical approaches. Significant mechanical hypersensitivity was induced in rats 2 d after SNL and lasted for >14 d. Compared with the sham-operated group, vlPAG slices from neuropathic rats 3 and 10 days after SNL displayed smaller EPSCs with prolonged latency, less frequent and smaller miniature EPSCs, higher paired-pulse ratio of EPSCs, smaller AMPAR-mediated EPSCs, smaller AMPA currents, greater NMDAR-mediated EPSCs, greater NMDA currents, lower AMPAR-mediated/NMDAR-mediated ratios, and upregulation of the NR1 and NR2B subunits, but not the NR2A, GluR1, or GluR2 subunits, of glutamate receptors. There were no significant differences between day 3 and day 10 neuropathic groups. These results suggest that SNL leads to hypoglutamatergic neurotransmission in the vlPAG resulting from both presynaptic and postsynaptic mechanisms. Upregulation of NMDARs might contribute to hypofunction of AMPARs via subcellular redistribution. Long-term hypoglutamatergic function in the vlPAG may lead to persistent reduction of descending pain inhibition, resulting in chronic neuropathic pain.

Differential regulation of glucocorticoid receptor expression in distinct columns of periaqueductal grey in rats with behavioural disability following nerve injury.

Neuropathic pain is diagnosed primarily by sensory dysfunction, which includes both spontaneous, and stimulus-evoked pain. Clinical evaluation highlights the disabilities which characterise this condition for most patients. Chronic constriction injury of the sciatic nerve (CCI) evokes sensory dysfunction characteristic of neuropathic pain. Approximately, 30 % of CCI rats show disabilities similar to those identified in clinical evaluation of neuropathic pain patients, these include: altered social behaviours; sleep disturbances; and endocrine dysfunction. The periaqueductal grey (PAG) is a nodal point in the brain circuits which regulate these functions, and undergoes a distinct set of neural and glial adaptations following CCI, in rats with disabilities. CCI increases corticosterone, which through its actions at the glucocorticoid receptor (GR), can trigger cellular adaptation. GR expression in PAG was quantified using qRT-PCR, Western blotting and immunohistochemical analyses and nerve-injured rats, with and without disabilities, were compared. Our data showed that the PAG of disabled rats has significantly increased expression of GR mRNA and protein. Further, this increased protein expression reflects contrasting patterns of change in GR expression in PAG subregions. The dorsolateral PAG had significant increases in the number of GR-immunoreactive (GR-IR) cells and the caudal lateral and ventrolateral PAG each had significant reductions in the number of GR-IR cells. These regional increases and decreases correlated with the degree of disability, as indicated by the degree of change in social behaviours. Our results suggest a role for altered PAG, GR-corticosterone interactions and their resultant cellular consequences in the expression of disabilities in a subpopulation of nerve-injured rats.

Fastigial nuclei surgical damage and focal midbrain disruption implicate PAG survival circuits in cerebellar mutism syndrome.

BACKGROUND: Pediatric postoperative cerebellar mutism syndrome (CMS) is a rare but well-known complication of medulloblastoma (Mb) resection with devastating effects on expressive language, mobility, cognition, and emotional regulation that diminishes quality of life for many Mb survivors. The specific anatomical and neuronal basis of CMS remains obscure. We address this issue by identifying patterns of surgical damage and secondary axonal degeneration in Mb survivors with CMS. METHODS: Children with Mb deemed high risk for CMS based on intraventricular location of the tumor had T1 images analyzed for location(s) of surgical damage using a specially developed algorithm. We used three complementary methods of spatial analysis to identify surgical damage linked to CMS diagnosis. Magnetization transfer ratio (MTR) images were analyzed for evidence of demyelination in anatomic regions downstream of the cerebellum, indicating neuronal dysfunction. RESULTS: Spatial analyses highlighted damage to the fastigial nuclei and their associated cerebellar cortices as the strongest predictors of CMS. CMS-related MTR decrease was greatest in the ventral periaqueductal gray (PAG) area and highly consistent in the left red nucleus. CONCLUSION: Our evidence points to disruption of output from the fastigial nuclei as a likely causal trigger for CMS. We propose that core CMS symptoms result from a disruption in the triggering of survival behaviors regulated by the PAG, including the gating of vocalization and volitional movement. The fastigial nuclei provide the densest output to the PAG from the cerebellum, thus sparing these structures may provide a greater likelihood of CMS prevention.

Atrophy of spared gray matter tissue predicts poorer motor recovery and rehabilitation response in chronic stroke.

BACKGROUND AND PURPOSE: Although the motor deficit after stroke is clearly due to the structural brain damage that has been sustained, this relationship is attenuated from the acute to chronic phases. We investigated the possibility that motor impairment and response to constraint-induced movement therapy in patients with chronic stroke may relate more strongly to the structural integrity of brain structures remote from the lesion than to measures of overt tissue damage. METHODS: Voxel-based morphometry analysis was performed on MRI scans from 80 patients with chronic stroke to investigate whether variations in gray matter density were correlated with extent of residual motor impairment or with constraint-induced movement therapy-induced motor recovery. RESULTS: Decreased gray matter density in noninfarcted motor regions was significantly correlated with magnitude of residual motor deficit. In addition, reduced gray matter density in multiple remote brain regions predicted a lesser extent of motor improvement from constraint-induced movement therapy. CONCLUSIONS: Atrophy in seemingly healthy parts of the brain that are distant from the infarct accounts for at least a portion of the sustained motor deficit in chronic stroke.

Progressive gray matter changes in patients with congenital central hypoventilation syndrome.

INTRODUCTION: Patients with congenital central hypoventilation syndrome (CCHS) show brain injury in areas that control chemosensory, autonomic, motor, cognitive, and emotion functions, which are deficient in the condition. Many of these abnormal characteristics are present from the neonatal period; however, it is unclear whether tissue injury underlying the characteristics progressively worsens with time. We hypothesized that several brain areas in subjects with CCHS would show increased gray matter volume loss over time. METHODS: We collected high-resolution T1-weighted images twice (4 years apart) from seven subjects with CCHS (age at first study, 16.1 ± 2.7 years; four males) and three control subjects (15.9 ± 2.1 years; three males) using a 3.0-Tesla magnetic resonance imaging (MRI) scanner, and evaluated regional gray matter volume changes with voxel-based morphometry (VBM) procedures. RESULTS: Multiple brain sites in CCHS, including frontal, prefrontal, insular, and cingulate cortices; caudate nuclei and putamen; ventral temporal and parietal cortices; and cerebellar cortices showed significantly reduced gray matter volume over time. Only limited brain areas, including sensory, temporal, and medullary regions, emerged with increased gray matter at the later age. DISCUSSION: Patients with CCHS show reduced gray matter volume with age progression in autonomic, respiratory, and cognitive regulatory areas, an outcome that may contribute to deterioration of functions found in the syndrome with increasing age.

Wernicke's encephalopathy in a patient with acute pancreatitis: unusual cortical involvement and marvelous prognosis.

Wernicke's encephalopathy (WE) is a severe neurological disorder caused by thiamine deficiency. Clinically, it is most frequently observed in people with alcohol abuse. WE, however, can occur in any clinical condition associated with malnutrition or thiamine deficiency. We present the case of a 47-year-old woman with prolonged therapeutic fasting who presented with ophthalmoplegia, ataxia and deep coma. MRI showed unusual symmetric cortical abnormalities in the frontal and parietal lobes, as well as typical lesions surrounding the third ventricle and aqueduct. Although the patient entered a vegetative state, she finally regained consciousness after thiamine supplementation unexpectedly. To the best of our knowledge, it has never been reported to date that the patient with WE in a vegetative state with cortical damage shows a marvelous prognosis, which prompts us to report this case. In the present report, we highlight the role of MRI in the diagnosis of acute WE.

Preoperative Acute Sleep Deprivation Causes Postoperative Pain Hypersensitivity and Abnormal Cerebral Function.

Preoperative sleep loss can amplify post-operative mechanical hyperalgesia. However, the underlying mechanisms are still largely unknown. In the current study, rats were randomly allocated to a control group and an acute sleep deprivation (ASD) group which experienced 6 h ASD before surgery. Then the variations in cerebral function and activity were investigated with multi-modal techniques, such as nuclear magnetic resonance, functional magnetic resonance imaging, c-Fos immunofluorescence, and electrophysiology. The results indicated that ASD induced hyperalgesia, and the metabolic kinetics were remarkably decreased in the striatum and midbrain. The functional connectivity (FC) between the nucleus accumbens (NAc, a subregion of the ventral striatum) and the ventrolateral periaqueductal gray (vLPAG) was significantly reduced, and the c-Fos expression in the NAc and the vLPAG was suppressed. Furthermore, the electrophysiological recordings demonstrated that both the neuronal activity in the NAc and the vLPAG, and the coherence of the NAc-vLPAG were suppressed in both resting and task states. This study showed that neuronal activity in the NAc and the vLPAG were weakened and the FC between the NAc and the vLPAG was also suppressed in rats with ASD-induced hyperalgesia. This study highlights the importance of preoperative sleep management for surgical patients.

EP1 receptor within the ventrolateral periaqueductal grey controls thermonociception and rostral ventromedial medulla cell activity in healthy and neuropathic rat.

The aim of this study was to investigate the expression of prostaglandin EP1 receptor within the ventrolateral periaqueductal grey (VL PAG). The role of VL PAG EP1 receptor in controlling thermonociception and rostral ventromedial medulla (RVM) activity in healthy and neuropathic rats was also examined. EP1 receptor was indeed found to be expressed within the VL PAG and co-localized with vesicular GABA transporter. Intra-VL PAG microinjection of ONO-DI-004, a selective EP1 receptor agonist, dose-dependently reduced tail flick latency as well as respectively increasing and decreasing the spontaneous activity of ON and OFF cells. Furthermore, it increased the ON cell burst and OFF cell pause. Intra-VL PAG prostaglandin E2 (PGE2) behaved similarly to ONO-DI-004. The effects of ONO-DI-004 and PGE2 were antagonized by intra-VL PAG L335677, a selective EP1 receptor antagonist. L335677 dose-dependently increased the tail flick latency and ongoing activity of the OFF cells, while reducing the ongoing ON cell activity. It also decreased the ON cell burst and OFF cell pause. In neuropathic rats using spare nerve injury (SNI) of the sciatic nerve model, EP1 receptor expression decreased in the VL PAG. However, ONO-DI-004 and L335677 were able to alter pain responses and ON and OFF cell activity, as they did in healthy animals. Collectively, these data show that within the VL PAG, EP1 receptor has a facilitatory effect on the nociceptive response and consistently affects RVM neuron activity. Thus, the blockade of EP1 receptor in the VL PAG leads to antinociception in neuropathic pain conditions, despite its down-regulation. The expression of EP1 receptor on GABAergic neurons is consistent with an EP1 receptor blockade-induced disinhibition of the antinociceptive descending pathway at VL PAG level.

[Functional brain mapping of pain perception]. / Imagerie fonctionnelle cérébrale appliquée à l'analyse des phénomènes douloureux.

In this review, we summarize the contribution of functional imaging to the question of nociception in humans. In the beginning of the 90's, brain areas supposed to be involved in physiological pain processes were almost exclusively the primary somatosensory area (SI), thalamus, and anterior cingulate cortex. In spite of these a priori hypotheses, the first imaging studies revealed that the main brain areas and those providing the most consistent activations in pain conditions were the insular and the SII cortices, bilaterally. This has been confirmed with other techniques such as intracerebral recordings of evoked potentials after nociceptive stimulations with laser showing a consistent response in the operculo-insular area which amplitude correlates with pain intensity. In spite of electrode implantations in other areas of the brain, only rare and inconsistent responses have been found outside the operculo-insular cortices. With electrical stimulation delivered directly in the brain, it has also been shown that stimulation in this area only--and not in other brain areas--was able to elicit a painful sensation. Thus, over the last 15 years, the operculo-insular cortex has been re-discovered as a main area of pain integration, mainly in its sensory and intensity aspects. In neuropathic pain also, these areas have been demonstrated as being abnormally recruited, bilaterally, in response to innocuous stimuli. These results suggest that plastic changes may occur in brain areas that were pre-defined for generating pain sensations. Conversely, when the brain activations concomitant to pain relief is taken into account, a large number of studies pointed out medial prefrontal and rostral cingulate areas as being associated with pain controls. Interestingly, these activations may correlate with the magnitude of pain relief, with the activation of the PAG, and, at least in some instances, with the involvement of endogenous opioids.

Periaqueductal gray inputs to the paraventricular nucleus of the thalamus: Columnar topography and glucocorticoid (in)sensitivity.

The ability to cope with a novel acute stressor in the context of ongoing chronic stress is of critical adaptive value. The hypothalamic-pituitary-adrenal (HPA) axis contributes to the integrated physiological and behavioural responses to stressors. Under conditions of chronic stress, the posterior portion of the paraventricular thalamic nucleus (pPVT) mediates the 'habituation' of HPA-axis responses, and also facilitates HPA-axis reactivation to novel acute stressors amidst this habituation. Since pPVT neurons are sensitive to the inhibitory effects of circulating glucocorticoids, a glucocorticoid-insensitive neural pathway to the pPVT is likely essential for this reactivation process. The pPVT receives substantial inputs from neurons of the periaqueductal gray (PAG) region, which is organised into longitudinal columns critical for processing acute and/or chronic stressors. We investigated the columnar organisation of PAG â†’ pPVT projections and for the first time determined their glucocorticoid sensitivity. Retrograde tracer injections were made into different rostro-caudal regions of the pPVT, and their PAG columnar inputs compared. Glucocorticoid receptor immunoreactivity (GR-ir) was quantified in these projection neurons. We found that the dorsolateral PAG projected most strongly to rostral pPVT and the ventrolateral PAG most strongly to the caudal pPVT. Despite abundant GR-ir in the PAG, we report a striking absence of GR-ir in PAG â†’ pPVT neurons. Our data suggests that these pathways, which are insensitive to the direct actions of circulating glucocorticoids, likely play an important role in both the habituation of HPA-axis to chronic stressors and its facilitation to acute stressors in chronically stressed rats.