Ventromedial Thalamic Nucleus Research Articles

Involvement of 5-HT1A receptors of the thalamic descending pathway in the analgesic effect of intramuscular heating-needle stimulation in a rat model of lumbar disc herniation.

Intramuscular (IM) heating-needle therapy, a non-painful thermal therapy, has been found to exert an analgesic effect via the thalamic ventromedial (VM) nucleus, solely by reducing the triggering threshold for descending inhibition; this could be modulated by intracephalic 5-hydroxytryptamine-1A (5-HT1A) receptors, rather than via the regular analgesia pathway. In this study, the effect and the potential serotonergic mechanism of IM heating-needle stimulation at 43°C were explored in the case of the pathological state of lumbar disc herniation (LDH). A modified classic rat model of LDH, induced via autologous nucleus pulposus implantation, was utilized. IM inner heating-needles were applied at the attachment point of skeletal muscle on both sides of the L4 and L5 spinous processes. WAY-100635 and 8-OH-DAPT, 5-HT1A receptor antagonist and agonist, were separately injected into the bilateral thalamic mediodorsal (MD) and VM nucleus via an intrathalamic catheter. Nociception was assessed by bilateral paw withdrawal reflexes elicited by noxious mechanical and heat stimulation. IM heating-needle stimulation at a temperature of 43°C for 30 or 45 min significantly relieved both mechanical and heat hyperalgesia in the rat model of LDH (P < 0.05). Heat hyperalgesia was found to be significantly enhanced by administration of WAY-100635 into the thalamic VM nucleus, blocking the effect of heating-needle stimulation in a dose-dependent manner (P < 0.05), while no effects were detected after injection into the thalamic MD nucleus (P > 0.05). Injection of 8-OH-DAPT into the thalamic MD nucleus exerted no modulating effects on either mechanical or heat hyperalgesia (P > 0.05). IM heating-needle stimulation at 43°C for 30 min may activate 5-HT1A mechanisms, via the thalamic VM nucleus, to attenuate hyperalgesia in a rat model of LDH. This innocuous form of thermal stimulation is speculated to selectively activate the descending inhibition mediated by the thalamic VM nucleus, exerting an analgesic effect, without the involvement of descending facilitation of the thalamic MD nucleus.

The mouse cortico\u2013basal ganglia\u2013thalamic network

The cortico–basal ganglia–thalamo–cortical loop is one of the fundamental network motifs in the brain. Revealing its structural and functional organization is critical to understanding cognition, sensorimotor behaviour, and the natural history of many neurological and neuropsychiatric disorders. Classically, this network is conceptualized to contain three information channels: motor, limbic and associative1–4. Yet this three-channel view cannot explain the myriad functions of the basal ganglia. We previously subdivided the dorsal striatum into 29 functional domains on the basis of the topography of inputs from the entire cortex5. Here we map the multi-synaptic output pathways of these striatal domains through the globus pallidus external part (GPe), substantia nigra reticular part (SNr), thalamic nuclei and cortex. Accordingly, we identify 14 SNr and 36 GPe domains and a direct cortico-SNr projection. The striatonigral direct pathway displays a greater convergence of striatal inputs than the more parallel striatopallidal indirect pathway, although direct and indirect pathways originating from the same striatal domain ultimately converge onto the same postsynaptic SNr neurons. Following the SNr outputs, we delineate six domains in the parafascicular and ventromedial thalamic nuclei. Subsequently, we identify six parallel cortico–basal ganglia–thalamic subnetworks that sequentially transduce specific subsets of cortical information through every elemental node of the cortico–basal ganglia–thalamic loop. Thalamic domains relay this output back to the originating corticostriatal neurons of each subnetwork in a bona fide closed loop.

Thalamic input to motor cortex facilitates goal-directed action initiation

SUMMARYPrompt execution of planned motor action is essential for survival. The interactions between frontal cortical circuits and the basal ganglia are central to goal-oriented action selection and initiation.1–4 In rodents, the ventromedial thalamic nucleus (VM) is one of the critical nodes that conveys the output of the basal ganglia to the frontal cortical areas including the anterior lateral motor cortex (ALM).5–9 Recent studies showed the critical role of ALM and its interplay with the motor thalamus in preparing sensory-cued rewarded movements, specifically licking.10–12 Work in primates suggests that the basal ganglia output to the motor thalamus transmits an urgency or vigor signal,13–15 which leads to shortened reaction times and faster movement initiation. As yet, little is known about what signals are transmitted from the motor thalamus to the cortex during cued movements and how these signals contribute to movement initiation. In the present study, we employed a tactile-cued licking task in mice while monitoring reaction times of the initial lick. We found that inactivation of ALM delayed the initiation of cued licking. Two-photon Ca2+ imaging of VM axons revealed that the majority of the axon terminals in ALM were transiently active during licking. Their activity was predictive of the time of the first lick. Chemogenetic and optogenetic manipulation of VM axons in ALM indicated that VM inputs facilitate the initiation of cue-triggered and impulsive licking in trained mice. Our results suggest that VM thalamocortical inputs increase the probability and vigor of initiating planned motor responses.

CB1-cannabinoid-, TRPV1-vanilloid- and NMDA-glutamatergic-receptor-signalling systems interact in the prelimbic cerebral cortex to control neuropathic pain symptoms

Neuropathic pain (NP) is a challenge due to our limited understanding of the mechanisms that initiate and maintain chronic pain. The prelimbic division (PrL) of the medial prefrontal cortex (mPFC) is an important area of the emotional and cognitive components of pain and pharmacological systems can interact into the neocortex to elaborate the chronic pain. This work aimed to investigate the pharmacological cross-talk between synaptic neurotransmission, neuroanatomical approaches and NP conditions. A bidirectional neural tract tracer, the 3000-molecular-weight biodextran (BDA) was microinjected into the PrL cortex. The mechanical withdrawal threshold (MWT) was recorded by a von Frey test, and the effect of prelimbic cortex CB1, NMDA, and TRPV1 receptor modulation was evaluated 21 days after chronic constriction injury (CCI) of the sciatic nerve in male Wistar rats. Microinjection of a bidirectional neurotracer in the PrL cortex showed connections with the lateral division of the mediodorsal thalamic nucleus (MDL), central division of the mediodorsal thalamic nucleus (MDC), centrolateral thalamic nucleus (CL), ventromedial thalamic nucleus (VM), and the paracentral thalamic nucleus (PC). In detail, AM251, a CB1 receptor antagonist (at 50, 100 and 200 pmol) microinjections intra-PrL cortex decreased the MWT. Administrations of 6-iodonordihydrocapsaicin (6-I-CPS), a transient receptor potential vanilloid type 1 (TRPV1) antagonist, at 3 nmol and the endocannabinoid anandamide (AEA) at 50 and 100 pmol increased the MWT. AEA at 200 pmol injected in the PrL cortex decreased the MWT, and this hyperalgesic effect was blocked by 6-I-CPS at 3 nmol. The AEA (at 100 pmol) anti-allodynic effect was attenuated by AM251 (at 5 pmol). The TRPV1 selective agonist N-oleoyldopamine (OLDA) at 10 μM decreased the MWT. The blockade of the NMDA receptor with LY235959 (at 8 nmol) and 6-I-CPS (at 3 nmol) reversed the OLDA (at 10 μM) hyperalgesic effect. These findings showed that the PrL cortex sends pathways to thalamic nuclei that can mediate the nociception. We also suggest that the PrL cortex is involved in the potentiation and maintenance of mechanical allodynia by NMDA and TRPV1 receptor activation and that attenuation of this allodynia depends on CB1 receptor activation during NP.

PD-1 Regulates GABAergic Neurotransmission and GABA-Mediated Analgesia and Anesthesia.

SummaryThe immune checkpoint inhibitor programmed cell death protein 1 (PD-1) plays a critical role in immune regulation. Recent studies have demonstrated functional PD-1 expression in peripheral sensory neurons, which contributes to neuronal excitability, pain, and opioid analgesia. Here we report neuronal expression and function of PD-1 in the central nervous system (CNS), including the spinal cord, thalamus, and cerebral cortex. Notably, GABA-induced currents in spinal dorsal horn neurons, thalamic neurons, and cortical neurons are suppressed by the PD-1-neutralizing immunotherapeutic Nivolumab in spinal cord slices, brain slices, and dissociated cortical neurons. Reductions in GABA-mediated currents in CNS neurons were also observed in Pd1−/− mice without changes in GABA receptor expression. Mechanistically, Nivolumab binds spinal cord neurons and elicits ERK phosphorylation to suppress GABA currents. Finally, both GABA-mediated analgesia and anesthesia are impaired by Pd1 deficiency. Our findings reveal PD-1 as a CNS-neuronal inhibitor that regulates GABAergic signaling and GABA-mediated behaviors.

A visual lamina in the medulla oblongata of the frog, Rana pipiens

We have discovered a lamina of visually responsive units in the medulla oblongata of the frog. It spans the entire medial aspect of the rostrocaudal length of the medulla and extends dorsoventrally from the cell-dense dorsal zone into the cell-sparse ventral zone. Most visual units within this lamina have large receptive fields, with the majority extending bilaterally in the frontal visual field. Most of these neurons are binocular, have no apparent directional preference, respond equally well to stimuli of a variety of shapes and sizes, and exhibit strong habituation. More medial locations in the visual lamina represent ipsilateral visual space while more lateral locations within the lamina represent contralateral visual space. Many units in the caudal aspect of the visual lamina are bimodal, responding to both visual and somatosensory stimuli. HRP tracing reveals inputs to the lamina from many primary and secondary visual areas in the midbrain and diencephalon. There is no area-by-area segregation of the projections to the visual lamina. For example, most parts of the tectum project across the visual lamina. The only spatial order in the visual lamina is that at more medial sites there tends to be more input from contralateral tectum; and at more lateral sites there tends to be more input from ipsilateral tectum. There is bilateral input to the visual lamina from tectum, tegmentum, posterior nucleus of the thalamus, posterior tuberculum, and ventromedial thalamic nucleus. There is ipsilateral input to the visual lamina from torus semicircularis, pretectum, nucleus of Bellonci, and ventrolateral thalamic nucleus. There is contralateral input to the visual lamina from basal optic complex. Collectively, these results show the presence of visual influences in regions of the medulla that likely represent an important step in sensorimotor transformation.

Effects of Heating-needle Stimulation in Restoration of Weakened Descending Inhibition of Nociception in a Rat Model of Parkinson’s Disease

Here we investigated variations of endogenous descending modulation of nociception and therapeutic effects of intramuscular (i.m.) heating-needle stimulation in early stage of Parkinson’s disease (PD) induced by unilateral microinjection of 3.5 μl of 2.5 μg/μl 6-hydroxydopamine into the rat striatum. Paw withdrawal reflexes to noxious mechanical and heat stimuli in PD rats with and without exposure to i.m. 5.8% saline induced muscle nociception were evaluated. Experimental PD had no influence on mechanical or heat sensitivity in the baseline condition, whereas descending facilitation was stronger and descending inhibition was weaker in PD rats than vehicle-treated or naive rats during muscle nociception (P < 0.05). Striatal administration of 5 μg of dopamine failed to reverse the PD-associated changes in descending facilitation or inhibition, whereas dopamine in the thalamic mediodorsal (MD) nucleus and ventromedial (VM) nucleus significantly decreased the increase in descending facilitation and reversed the attenuation in descending inhibition, respectively (P < 0.05). I.m. 43 °C of heating-needle stimulation had no effects on the enhanced descending facilitation in PD rats, but it markedly increased descending inhibition and reversed the increase in the number of apomorphine-induced body rotations (P < 0.05), which effects were dose-dependently attenuated by raclopride, a dopamine 2 receptor antagonist, in the thalamic VM nucleus (P < 0.05). The results indicate that the early-stage PD is associated with enhanced descending facilitation and weakened descending inhibition. From clinical perspective, 43 °C heat therapeutic regime promises to selectively enhance descending inhibition that is accompanied by improvement of motor dysfunction in PD.

Afferent and efferent connections of the nucleus prethalamicus in the yellowfin goby Acanthogobius flavimanus.

The nucleus prethalamicus (PTh) receives fibers from the optic tectum and then projects to the dorsal telencephalon in the yellowfin goby Acanthogobius flavimanus. However, it remained unclear whether the PTh is a visual relay nucleus, because the optic tectum receives not only visual but also other sensory modalities. Furthermore, precise telencephalic regions receiving prethalamic input remained unknown in the goby. We therefore investigated the full set of afferent and efferent connections of the PTh by direct tracer injections into the nucleus. Injections into the PTh labeled cells in the optic tectum, ventromedial thalamic nucleus, central and medial parts of the dorsal telencephalon, and caudal lobe of the cerebellum. We found that the somata of most tecto-prethalamic neurons are present in the stratum periventriculare. Their dendrites ascend to reach the major retinorecipient layers of the tectum. The PTh is composed of two subnuclei (medial and lateral) and topographic organization was appreciated only for tectal projections to the lateral subnucleus (PTh-l), which also receives sparse retinal projections. In contrast, the medial subnucleus receives fibers only from the medial tectum. We found that the PTh projects to nine subregions in the dorsal telencephalon and four in the ventral telencephalon. Furthermore, cerebellar injections revealed that cerebello-prethalamic fibers cross the midline twice to innervate the PTh-l on both sides. The present study is the first detailed report on the full set of the connections of PTh, which suggests that the PTh relays visual information from the optic tectum to the telencephalon.

Effects of Intramuscular Heating-needle Stimulation in Controlling Adjuvant-induced Muscle Nociception in Rats: Differential Roles of Thalamic Purinergic P2X3 Receptors

Here we investigated effects of intramuscular (i.m.) heating-needle stimulation on persistent muscle nociception evoked by i.m. injection of different doses (50–200 µl) of complete Freund’s adjuvant (CFA) in rats. Paw withdrawal reflexes evoked by noxious mechanical and heat stimulation as well as hind limb swelling were determined prior to and two weeks after the CFA injection. The unilateral injection of CFA induced a dose-related and long-lasting (5–14 d), bilateral secondary mechanical hyperalgesia and heat hypoalgesia associated with long-term limb swelling. A period of 30–45 min 43 °C heating-needle stimulation significantly enhanced the i.m. CFA-induced bilateral heat hypoalgesia and alleviated hind limb swelling. In contrast, 30–45 min 46 °C heating-needle stimulation markedly enhanced both mechanical hyperalgesia and heat hypoalgesia, but failed to influence the CFA-induced hind limb swelling. Microinjection of P2X3 receptor antagonist A-317491 (0.5–4.5 nmol/0.5 µl) into the thalamic ventromedial (VM) nucleus dose-dependently inhibited the 43 °C and 46 °C heating-needle stimulation-induced heat hypoalgesia, whereas the 46 °C heating-needle stimulation-induced mechanical hyperalgesia was significantly prevented by microinjection of A-317491 into the thalamic mediodorsal (MD) nucleus. In contrast, the hind limb swelling was not affected by the microinjection of A-317491 into the thalamic VM or MD nucleus. The present study indicates that in the CFA-induced persistent muscle nociception condition, 43 °C heating-needle stimulation selectively increases descending inhibition, which effect is modulated by the thalamic VM nucleus. In addition to the antinociceptive role of P2X3 receptors in the thalamic VM nucleus, P2X3 receptors within the thalamic MD nucleus participate in the descending facilitation evoked by i.m. 46 °C heating-needle stimulation.

Leucine-enkephalin-immunoreactive neurons in the brain of the cichlid fish Oreochromis mossambicus

Enkephalins are the pentapeptides involved in pain relief and neuroendocrine responses with high affinity for delta opioid receptors in vertebrates. In the present investigation, we studied the distribution of leucine-enkephalin-immunoreactive (L-ENK-ir) neurons in the brain of the cichlid fish Oreochromis mossambicus. Application of the antisera against L-ENK revealed the presence of numerous L-ENK-ir perikarya and fibres in subdivisions of the dorsal and the ventral telencephalon, the medial olfactory tract and the nucleus entopeduncularis, whereas intensely labelled L-ENK-ir fibres were noticed in the olfactory bulb. Furthermore, the presence of L-ENK-ir cells and dense accumulations of fibres in the preoptic area and its subdivisions, the nucleus preopticus pars magnocellularis and the nucleus preopticus pars parvocellularis suggested a role for this peptide in regulation of reproduction. While intensely labelled cells and fibres were found in the nucleus lateralis tuberis pars lateralis as well as the nucleus lateralis tuberis pars medialis, some L-ENK-ir fibres were seen at the hypothalamo-hypophyseal tract indicating the possible hypophysiotrophic role for this peptide. Numerous L-ENK-ir cells and dense network of fibres were observed in the subdivisions of the nucleus recess lateralis and the pretectal area, whereas intensely labelled thick network of L-ENK- fibres were found in the ventromedial thalamic nucleus, the sub-layers of the optic tectum and the rostral spinal cord. The widespread distribution of L-ENK-immunoreactivity in the olfactory bulb, the telencephalon, the diencephalon and the mesencephalon regions of the brain as well as the spinal cord suggests the possible involvement of this peptide in the regulation of diverse functions such as neuroendocrine, antinociceptive, visual and olfactory responses in O. mossambicus.

Activation of parvalbumin interneurons in anterior cingulate cortex impairs observational fear

The ability to detect conspecific’s distress is crucial for animal survival. In rodent models, observational fear (OF) occurs when one animal perceives another fear related negative emotions, which may model certain behaviors caused by witnessing traumatic experiences in humans. Anterior cingulate cortex (ACC) has been showed to play a crucial role in OF. However, cellular and neural circuit basis relating to ACC governing OF is poorly understood. Here, we used Designer Receptor Exclusively Activated by a Designer Drug (DREADD) system to investigate the cell type specific circuit mechanism of ACC in OF. Firstly, inhibitory hM4D (Gi) designer receptor together with clozapine N-oxide (CNO) injection was applied to inactivate ACC neurons in the observer mice. We found that, chemogenetic inhibition of ACC resulted in a decreased freezing response in the observer mice. Next, combining PV-ires-Cre mice and Cre-dependent DREADD system, we selectively targeted the ACC parvalbumin (PV) interneurons with the excitatory hM3D (Gq) designer receptor. Activation of ACC PV interneurons following CNO injection reduced freezing response in the observer mice, while had no effect on freezing response in the demonstrator mice. Finally, monosynaptic rabies retrograde tracing revealed that ACC PV interneurons receive inputs from the mediodorsal thalamic nucleus (MD) and the ventromedial thalamic nucleus (VM), both known for their roles in OF. Taken together, these findings reveal that ACC activation is important for OF, during which PV interneurons in ACC play an important regulatory role. Abnormal function of ACC PV interneurons might contribute to the pathology of empathy- deficits related diseases, such as autism and schizophrenia.

Regulation of cortical activity and arousal by the matrix cells of the ventromedial thalamic nucleus

The “non-specific” ventromedial thalamic nucleus (VM) has long been considered a candidate for mediating cortical arousal due to its diffuse, superficial projections, but direct evidence was lacking. Here, we show in mice that the activity of VM calbindin1-positive matrix cells is high in wake and REM sleep and low in NREM sleep, and increases before cortical activity at the sleep-to-wake transition. Optogenetic stimulation of VM cells rapidly awoke all mice from NREM sleep and consistently caused EEG activation during slow wave anesthesia, while arousal did not occur from REM sleep. Conversely, chemogenetic inhibition of VM decreased wake duration. Optogenetic activation of the “specific” ventral posteromedial nucleus (VPM) did not cause arousal from either NREM or REM sleep. Thus, matrix cells in VM produce arousal and broad cortical activation during NREM sleep and slow wave anesthesia in a way that accounts for the effects classically attributed to “non-specific” thalamic nuclei.

Noninvasive neuromodulation and thalamic mapping with low-intensity focused ultrasound

OBJECTIVE Ultrasound can be precisely focused through the intact human skull to target deep regions of the brain for stereotactic ablations. Acoustic energy at much lower intensities is capable of both exciting and inhibiting neural tissues without causing tissue heating or damage. The objective of this study was to demonstrate the effects of low-intensity focused ultrasound (LIFU) for neuromodulation and selective mapping in the thalamus of a large-brain animal. METHODS Ten Yorkshire swine ( Sus scrofa domesticus) were used in this study. In the first neuromodulation experiment, the lemniscal sensory thalamus was stereotactically targeted with LIFU, and somatosensory evoked potentials (SSEPs) were monitored. In a second mapping experiment, the ventromedial and ventroposterolateral sensory thalamic nuclei were alternately targeted with LIFU, while both trigeminal and tibial evoked SSEPs were recorded. Temperature at the acoustic focus was assessed using MR thermography. At the end of the experiments, all tissues were assessed histologically for damage. RESULTS LIFU targeted to the ventroposterolateral thalamic nucleus suppressed SSEP amplitude to 71.6% ± 11.4% (mean ± SD) compared with baseline recordings. Second, we found a similar degree of inhibition with a high spatial resolution (∼ 2 mm) since adjacent thalamic nuclei could be selectively inhibited. The ventromedial thalamic nucleus could be inhibited without affecting the ventrolateral nucleus. During MR thermography imaging, there was no observed tissue heating during LIFU sonications and no histological evidence of tissue damage. CONCLUSIONS These results suggest that LIFU can be safely used to modulate neuronal circuits in the central nervous system and that noninvasive brain mapping with focused ultrasound may be feasible in humans.

Evaluation of Possible “Impulsivity” Following Ventromedial Thalamic Nucleus Deactivation in the Rat Using a Fixed Consecutive Number Task (P6.209)

Evaluation of Possible “Impulsivity” Following Ventromedial Thalamic Nucleus Deactivation in the Rat Using a Fixed Consecutive Number Task (P6.209)

Distribution of endomorphin-like-immunoreactive neurones in the brain of the cichlid fish Oreochromis mossambicus.

Endomorphins (EMs) are tetrapeptides involved in pain and neuroendocrine responses with a high affinity for μ-opioid receptors in mammals. In the present study, we investigated the distribution of EM-like-immunoreactive (EM-L-IR) neurones in the brain of the cichlid fish Oreochromis mossambicus. Application of antisera against EM-1 and 2 (EM-1-2) revealed the presence of EM-L-IR somata and fibres throughout the different subdivisions of the olfactory bulb, such as the olfactory nerve layer and the granule cell layer. Although the extensions of EM-L-IR fibres were seen along the medial olfactory tract, intensely labelled EM-L-IR somata were found in different subdivisions of the telencephalon. In the diencephalon, intensely stained EM-L-IR neurones were noted in the preoptic area, the nucleus preopticus pars magnocellularis, the suprachiasmatic nucleus, the nucleus lateralis tuberis pars lateralis and the nucleus lateralis tuberis pars medialis regions, whereas projections of EM-L-IR fibres were also seen along the hypothalamic-hypophyseal tract, suggesting a possible hypophysiotrophic role for these neurones. Intense to moderately stained EM-L-IR neurones were noted in different subdivisions of thalamic nucleus, such as the dorsal posterior thalamic nucleus, commissura posterior, ventromedial thalamic nucleus, nucleus posterior tuberis, ventrolateral thalamic nucleus and medial preglomerular nucleus. Numerous intensely stained perikarya and axonal fibres were also noted throughout the inferior lobe, along the periventricular margin of the reccessus lateralis and in the nucleus recesus lateralis regions. In addition, numerous moderately labelled EM-like neuronal populations were found in the secondary gustatory nucleus and rostral spinal cord. The widespread distribution of EM-L-IR neurones throughout the brain and spinal cord indicates the diverse roles for these cells in neuroendocrine and neuromodulatory responses for the first time in fish. The present study provides further insights into the possible existence of EM-like peptides in early vertebrate lines and suggests that these peptides might have been well-conserved during the course of evolution.

Role of thalamic nuclei in the modulation of Fos expression within the cerebral cortex during hypertonic saline-induced muscle nociception.

It has been proposed that thalamic mediodorsal (MD) and ventromedial (VM) nuclei form thalamic 'nociceptive discriminators' in discrimination of nociceptive afferents, and specifically govern endogenous descending facilitation and inhibition. The present study conducted in rats was to explore the role of thalamic MD and VM nuclei in modulation of cerebral neuronal activities by means of detection of spatiotemporal variations of Fos expression within the cerebral cortex. Following a unilateral intramuscular injection of 5.8% saline into the gastrocnemius muscle, Fos expression within the bilateral, different areas of the cerebral cortex except S2 was significantly increased (P<0.05). Particularly, the increases in Fos expression within the cingulate cortex and the insular cortex occurred at 0.5h, 4h and reached the peak level at 4h, 16h, respectively. Electrolytic lesion of the contralateral thalamic MD and VM nuclei significantly blocked the 5.8% saline intramuscularly induced increases in Fos expression within the bilateral cingulate and insular cortices, respectively. Additionally, the 5.8% saline-induced Fos expression in the cingulate cortex and the insular cortex were dose-dependently attenuated by microinjection of μ-opioid antagonist β-funaltrexamine hydrochloride into the thalamic MD and VM nuclei. It is suggested that (1) the neural circuits of 'thalamic MD nucleus - cingulate cortex' and 'thalamic VM nucleus - insular cortex' form two distinct pathways in the endogenous control of nociception, (2) mirror or contralateral pain is hypothesized to be related to cross-talk of neuronal activities within the bilateral cerebral cortices modulated by μ-opioid receptors within the thalamic MD and VM nuclei.

Changes in the expression of genes encoding for mGlu4 and mGlu5 receptors and other regulators of the indirect pathway in acute mouse models of drug-induced parkinsonism

Neuroadaptive changes involving the indirect pathway of the basal ganglia motor circuit occur in the early phases of parkinsonism. The precise identification of these changes may shed new light into the pathophysiology of parkinsonism and better define the time window of pharmacological intervention. We examined some of these changes in mice challenged with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), or with the dopamine receptor blocker, haloperidol. These two models clearly diverge from Parkinson's disease (PD); however, they allow an accurate time-dependent analysis of neuroadaptive changes occurring in the striatum. Acute haloperidol injection caused a significant increase in the transcripts of mGlu4 receptors, CB1 receptors and preproenkephalin-A at 2 and 24 h, and a reduction in the transcripts of mGlu5 and A2A receptors at 2 h. At least changes in the expression of mGlu4 receptors might be interpreted as compensatory because haloperidol-induced catalepsy was enhanced in mGlu4−/− mice. Mice injected with 30 mg/kg of MPTP also showed an increase in the transcripts of mGlu4 receptors, CB1 receptors, and preproenkephalin-A at 3 d, and a reduction of the transcript of A2A receptors at 1 d in the striatum. Genetic deletion of mGlu4 receptors altered the functional response to MPTP, assessed by counting c-Fos+ neurons in the external globus pallidus and ventromedial thalamic nucleus. These findings offer the first evidence that changes in the expression of mGlu4 and mGlu5 receptors occur in acute models of parkinsonisms, and lay the groundwork for the study of these changes in models that better recapitulate the temporal profile of nigrostriatal dysfunction associated with PD.

Descending controls: how to harness for the relief of pain?

Descending control of spinal nociception, which originates in many brain regions, is a major determinant of the pain experience. Descending control is dynamic and can either depress or enhance spinal nociceptive signalling depending on where it originates or what triggers it (Heinricher et al. 2009). A major challenge for therapeutic utility, whether that be engaged by physical or chemical means, is to harness the beneficial aspects of descending control. Descending inhibitory and facilitatory controls are widely reported to be activated by noxious stimulation of spino-bulbo-spinal circuits (Ossipov et al. 2014). Inhibitory control mediates antinociception and descending facilitation is pronociceptive. There is evidence to support the view that descending facilitation is engaged at lower nociceptive stimulus intensities than that required to trigger descending inhibition (You et al. 2010). Wherein lies the problem: how to engage the beneficial inhibitory controls alone. Nociceptive stimuli are conveyed to the spinal cord in A- and C-fibre afferents. An often overlooked issue with respect to descending control of spinal nociception is that C-fibre afferents also convey information about thermal stimuli and a significant unknown, which is addressed in the paper from Hao-Jun You's laboratory in this issue of The Journal of Physiology, is the extent to which non-noxious thermal stimulation, conveyed in C-fibres, may activate descending pain control systems (You et al. 2014). Moxibustion is a therapeutic strategy that has been used in oriental medicine for more than 2000 years. It is the practice of applying non-noxious thermal stimuli for the treatment of a number of disorders including pain (Bonica, 1974). In contrast to diffuse noxious inhibitory controls (DNIC; Le Bars et al. 1979), this paper provides novel experimental evidence to explain how non-noxious heat stimuli may harness potentially therapeutic mechanisms for the relief of pain. The paper also extends previous work from this laboratory (You et al. 2013) that relates to the role of different thalamic nuclei (mediodorsal and ventromedial nuclei) in the control of spinal nociception. Important advances of potential therapeutic relevance are twofold: (i) inhibitory control from the thalamic ventromedial nuclei is activated by both noxious (46°C) and non-noxious stimuli (43°C) whereas facilitatory control from the thalamic mediodorsal nucleus is activated by noxious stimulation alone, and (ii) these two thalamic nuclei are chemically distinct with respect to their opioid sensitivity; descending inhibition from the thalamic ventromedial nucleus elicited by non-noxious heat stimuli (43°C) is selectively δ-opioid receptor dependent, unlike nociceptive-evoked controls from the thalamic ventromedial nucleus which are μ-, δ-, and κ−opioid sensitive. Descending facilitation from the thalamic mediodorsal nucleus is μ-opioid receptor dependent, providing a new context in which to interpret μ-opioid-mediated analgesia followed by hyperalgesia. As such, these findings provide novel insights into pain control mechanisms that are of potential therapeutic relevance.

Influence of intramuscular heat stimulation on modulation of nociception: complex role of central opioid receptors in descending facilitation and inhibition.

It has been reported that the threshold to activate 'silent' or inactive descending facilitation of nociception is lower than that of descending inhibition. Thus, the development of pain therapy to effectively drive descending inhibition alone, without the confounding influences of facilitation is a challenge. To address this issue we investigated the effects of intramuscular stimulation with a heating-needle on spinal nociception, assessed by measuring nociceptive paw withdrawal reflex in rats. Additionally, involvement of the thalamic 'nociceptive discriminators' (thalamic mediodorsal (MD) and ventromedial (VM) nuclei), and opioid-mediated mechanisms were further explored. Descending facilitation and inhibition were elicited by 46°C noxious heating-needle stimulation, and were regulated by thalamic MD and VM nuclei, respectively. In contrast, innocuous heating-needle stimulation at a temperature of 43°C elicited descending inhibition modulated by the thalamic VM nucleus alone. Microinjection of μ/δ/κ-opioid receptor antagonists β-funaltrexamine hydrochloride/naltrindole/nor-binaltorphimine, into the VM nucleus attenuated the 46°C intramuscular heating-needle stimulation-evoked descending inhibition, whereas treatment of the MD nucleus with β-funaltrexamine hydrochloride significantly decreased the descending facilitation. By contrast, descending inhibition evoked by 43°C heating-needle stimulation was only depressed by naltrindole, as opposed to μ- and κ-opioid receptor antagonists, which failed to influence descending inhibition. The present study reveals distinct roles of μ-opioid receptors in the function of thalamic MD and VM nuclei,which exert facilitatory and inhibitory actions on nociception. Furthermore, innocuous, but not noxious, intramuscular heating-needle stimulation targeting δ-opioid receptors is suggested to be a promising avenue for the effective inhibition of pain.

Temperature dependent changes in cocaine- and amphetamine regulated transcript (CART) peptide in the brain of tadpole, Sylvirana temporalis

Cocaine- and amphetamine-regulated transcript peptide (CARTp) has emerged as a novel neurotransmitter in the brain. Although the physiological role of the peptide has been intensely investigated in mammals, its role in amphibians has not been investigated. In the present study, an attempt has been undertaken to study the expression of CART in the tadpole brain of frog Sylvirana temporalis, subjected to thermal stress. Cells with strong CART-immunoreactivity were observed in the nucleus preoptic area (NPO) of tadpoles exposed to high temperature (37±2°C) as compared to those in the tadpoles exposed to low (12±2°C) and normal (24±2°C) temperatures. In the ventromedial thalamic nucleus (VM) and nucleus posterocentralis thalami (NPC), moderate CART-ir cells were observed in the control groups while number of cells and intensity of immunoreactivity was increased in tadpoles at low and high temperatures. In the nucleus infundibularis ventralis (NIV) and raphe nucleus (RA), CART immunoreactivity increased in the low as well as high temperature treated groups. Intensely stained CART cells were observed in the pituitary of tadpoles exposed to high temperature as compared to low temperature and control groups. We suggest that CART system in the brain and pituitary of tadpole may play a very important role in mediating responses to temperature variations in the environment.