Stimulation Of Lateral Hypothalamus Research Articles

Restoring the firing activity of ventral tegmental area neurons by lateral hypothalamic deep brain stimulation following morphine administration in rats

We have previously shown that high-frequency deep brain stimulation (DBS) of the lateral hypothalamus (LH) compromises morphine-induced addiction-like behavior in rats. The exact mechanism underlying this effect is not known. Here, we investigated the assumption that DBS in the LH influences the firing activity of neurons in the ventral tegmental area (VTA). To that end, male Wistar rats received morphine (5 mg/kg; s.c.) for three days and underwent extracellular single unit recording under general anesthesia one day later. During the recording, the rats received an intraoperative injection of morphine (5 mg/kg; s.c.) plus DBS in the LH (130 Hz pulse frequency, 150 μA amplitude, and 100 μs pulse width). One group of animals also received preoperative DBS after each morphine injection before the recording. The spiking frequency of VTA neurons was measured at three successive phases: (1) baseline (5–15 min); (2) DBS-on (morphine + DBS for 30 min); and (3) After-DBS (over 30 min after termination of DBS). Results showed that morphine suppressed the firing activity of a large population of non-DA neurons, whereas it activated most DA neurons. Intraoperative DBS reversed morphine suppression of non-DA firing, but did not alter the excitatory effect of morphine on DA neurons firing. With repeated preoperative application of DBS, non-DA neurons returned to the morphine-induced suppressive state, but DA neurons released from the excitatory effect of morphine. It is concluded that the development of morphine reward is associated with a hypoactivity of VTA non-DA neurons and a hyperactivity of DA neurons, and that DBS modulation of the spiking activity may contribute to the blockade of morphine addiction-like behavior.

Involvement of dopaminergic system in the dentate gyrus of the hippocampus in modulating the orofacial pain-related behaviors in the rats.

Chemical stimulation of the lateral hypothalamus (LH) induces analgesia by forming neural circuitries with multiple brain regions. The involvement of hippocampal dopaminergic receptors in the LH stimulation-induced antinociception in specific pain models in animals has been documented. However, because the neural circuitries involved in the mediation of orofacial pain are not the same as those that mediate the other types of pain, the present study aims to detect the role of dopamine receptors within the dentate gyrus (DG) in the antinociceptive responses induced by LH stimulation in an animal model of orofacial pain. Male Wistar rats (220-250 g) were implanted with two separate cannulae into the LH and DG on the same side. D1- or D2-like dopamine receptor antagonist, SCH23390, or sulpiride (0.25, 1, and 4 μg) were microinjected into the DG, five minutes before intra-LH injection of carbachol (250 nM). The animals were then injected with formalin 1% (50 μL; sc) into the upper lip lateral to the nose and subjected to the orofacial formalin test. Intra-DG administration of SCH23390 or sulpiride attenuated the antinociceptive responses induced by intra-LH microinjection of carbachol during the orofacial formalin test. The findings of the current study suggest that chemical stimulation of the LH modulates orofacial pain, possibly through activation of the DG dopaminergic neurons. Due to the high incidence and prevalence of orofacial pain in the general population, understanding how such neuronal circuitry modulates nociceptive processing will advance the search for novel therapeutics.

Involvement of Dopaminergic System in the Dentate Gyrus of the Hippocampus in Modulating the Orofacial Pain-Related Behaviors in the Rats

Chemical stimulation of the lateral hypothalamus (LH) induces analgesia by formation neural circuitries with multiple brain regions. The involvement of hippocampal dopaminergic receptors in the LH stimulation-induced antinociception in certain animal models of pain has been documented, however, considering the fact that the neural circuitries involved in the mediation of orofacial pain are not the same as those that mediate the other types of pain, the present study aims to detect the role of dopamine receptors within the dentate gyrus (DG) in the antinociceptive responses induced by LH stimulation in an animal model of orofacial pain. Male Wistar rats (220-250 g) were implanted with two separate cannulae into the LH and DG on the same side. D1- or D2-like dopamine receptor antagonist, SCH23390 or Sulpiride (0.25, 1, and 4 μg) were microinjected into the DG, five minutes prior to intra-LH injection of carbachol (250 nM). The animals were then injected with formalin 1% (50 μl; sc) into the upper lip lateral to the nose and subjected to the orofacial formalin test. Intra-DG administration of SCH23390 or Sulpiride attenuated the antinociceptive responses induced by intra-LH microinjection of carbachol during orofacial formalin test. The findings of the current study suggest that chemical stimulation of the LH modulates the orofacial pain possibly through activation of the DG dopaminergic neurons. Due to the high incidence and prevalence of orofacial pain in the general population, understanding how such neuronal circuitry modulates nociceptive processing will advance the search for novel therapeutics.

The blockade of μ‑opioid receptors in the lateral hypothalamus enhances panic attack‑like behaviour and diminishes defensive antinociception.

The lateral hypothalamus (LH) sends neural pathways to structures involved on predator‑related defensive behaviours, escape and antinociception. The aim of this study was to investigate the role played by μ-opioid receptors located on LH neurons in defensive behaviour and unconditioned fear‑induced antinociception elicited by electric stimulation of LH. To achieve the goals, the μ1-opioid receptor selective antagonist naloxonazine was administered at different concentrations in the LH, and the defensive behaviour and fear‑induced antinociception elicited by electrical stimulation of LH were evaluated. The electrical stimulation of LH caused escape behaviour followed by defensive antinociception. Microinjections of naloxonazine in a concentration of 5.0 μg/0.2 μL in the LH decreased the aversive stimulus‑induced escape behaviour thresholds, but diminished defensive antinociception. These findings suggest that μ-opioid receptors of LH can be critical to panic attack‑related symptoms and facilitate the unconditioned fear‑induced antinociception produced by LH neurons activation.

Blocking the dopaminergic receptors in the hippocampal dentate gyrus reduced the stress-induced analgesia in persistent inflammatory pain in the rat

Although the dentate gyrus (DG) as a component of the hippocampal formation has been well known for its role in memory, various studies showed a diverse population of unique cell types and various inputs and outputs in this region. Besides, brain dopamine is known for its roles in reward, motivation, pleasure, and being involved in the pain process. Further, previous studies demonstrated the participation of DG dopaminergic receptors in antinociception induced by lateral hypothalamus stimulation. This study aimed to investigate the role of DG dopaminergic receptors (D1- and D2-like dopamine receptors) in stress-induced analgesia (SIA) using the formalin test as a persistent inflammatory pain model. One hundred two male Wistar rats were unilaterally implanted with a cannula into the DG. Animals received an intra-DG infusion of SCH23390 (0.25, 1, and 4 μg/rat), or Sulpiride (0.25, 1, and 4 μg/rat) as D1- and D2-like dopamine receptor antagonists, respectively, five min before exposure to forced swim stress (FSS). Ten minutes after FSS termination, 2.5% formalin solution as an inflammatory agent was subcutaneously injected into the plantar surface of the hind paw, and the pain score was quantified for one hour. The findings revealed that exposure to FSS produced SIA, though this FSS-induced analgesia was attenuated in the early and late phase of the formalin test by intra-DG microinjection of SCH23390 or Sulpiride. These results suggested that both D1- and D2-like dopamine receptors in the DG have a considerable role in analgesia induced by FSS.

Role of the Orexinergic System Within the Ventral Tegmental Area in the Development of Sensitization to Morphine Induced by Lateral Hypothalamus Stimulation.

The Lateral Hypothalamus (LH) has long been known to implicate the addictive behaviors of drug abuse. The Ventral Tegmental Area (VTA) is a major area of the mesolimbic system that is strongly involved in developing morphine sensitization. The current study aimed to examine the role of intra-VTA orexin receptors in the LH stimulation-induced sensitization to the antinociceptive response of morphine. A total of 114 adult male Wistar rats underwent unilateral implantation of two separate cannulae in the LH and VTA using the stereotaxic apparatus. Intra-VTA administration of the Orexin-1 (OX1) and Orexin-2 (OX2) receptor antagonists, SB334867 and TCS OX2 29 (1, 3, and 10 nM/0.3 μL DMSO), respectively, was performed 5 min before concurrent microinjection of carbachol (250 nM/0.5 μL saline) into the LH and an ineffective dose of morphine (0.5 mg/kg; SC) during a 3-day sensitization period. After a 5-day free drug period, on the ninth day, for assessing the morphine sensitization, the nociceptive response was measured before and after morphine injection (1 mg/kg; SC) using the tail-flick test. The results revealed that the concurrent administration of carbachol (250 nM) and an ineffective dose of morphine significantly induced morphine sensitization. Besides, the blockade of OX1 and OX2 receptors within the VTA before intra-LH carbachol injection attenuated morphine sensitization. These findings suggest that LH stimulation potentiates the sensitization to morphine antinociceptive responses via affecting orexin receptors located in the VTA. However, OX1 receptors contribute more than OX2 receptors in the VTA to morphine sensitization in rats. LH stimulation enhances sensitization to the ineffective dose of morphineIntra-VTA OX1 receptor involves in morphine sensitization-induced by LH stimulationIntra-VTA OX2 receptor involves in morphine sensitization-induced by LH stimulation. Behavioral sensitization, such as sensitization to the antinociceptive response of drugs, which defines as an enhanced systemic reaction to the same dose of addictive drugs, occurs in response to continuous and intermittent administration of these drugs. The Lateral Hypothalamus (LH) sends the orexinergic projections to the various regions of the brain and stimulation of LH induces sensitization to the antinociceptive response of morphine. The Ventral tegmental area (VTA) is a region of the brain that is strongly involved in developing morphine sensitization and receives orexinergic projections of LH. The current study aimed to examine the role of orexin receptors within the VTA in the LH stimulation-induced sensitization to the antinociceptive response of morphine in rats. In this study orexin-1 (OX1) and orexin-2 (OX2) receptors within the VTA region were blocked using their antagonists. After five minutes chemical stimulation of LH was done using carbachol microinjection into this area and ineffective dose of morphine was injected subcutaneously. These interventions were done for three consecutive days as sensitization period. After a 5-day free drug period, on the ninth day, for assessing the morphine sensitization, the nociceptive response was measured. The results revealed that the concurrent administration of LH stimulation and an ineffective dose of morphine significantly induced morphine sensitization. Besides, the blockade of OX1 and OX2 receptors within the VTA before LH stimulation attenuated sensitization to the antinociceptive response of morphine. Therefore, the orexinergic system plays an important role in morphine sensitization and can be considered as one of the potential targets to increase the analgesic effect of morphine.

Role of D1- and D2-like dopamine receptors within the dentate gyrus in antinociception induced by chemical stimulation of the lateral hypothalamus in an animal model of acute pain

The dentate gyrus (DG) as the main gateway of the hippocampal formation (HF) plays a crucial role in pain modulation. For this purpose, the HF receives dopaminergic inputs originated from the substantia nigra and the ventral tegmental area. It has previously been shown that the lateral hypothalamus (LH) stimulation produces antinociception via orexinergic projections of the LH to the DG region. So, given the presence of dopamine receptors in the DG and the undeniable role of the dopaminergic system in pain modulation, the current study was conducted to investigate the role of dopamine receptors located within the DG in the LH stimulation-induced pain modulation. Adult male Wistar rats weighing 220–250 g were unilaterally implanted with two separate cannulas into the LH and DG. Intra-DG administration of D1- or D2-like dopamine receptor antagonist (0.125, 0.25, 1, and 4 µg) was performed just 5 min before chemical stimulation of the LH by carbachol (250 nM). Nociceptive assay was done using the tail-flick apparatus immediately after the last microinjection. The results demonstrated that the administration of SCH23390 or Sulpiride into the DG decreased the intra-LH carbachol-induced antinociceptive responses and decreased the tail-flick latency times. The role of D2-like dopamine receptor of the DG was more prominent than that of D1-like dopamine receptor in antinociceptive response produced by the LH stimulation. It seems to be a complex neural circuitry in which the LH produces antinociceptive effects, in part, via dopamine receptors located in the DG region.

Features of the involvement of the dopamine and serotonin brain systems in positive and negative emotional states in rats

The aim was to study the effect of rewarding and aversive stimulation of lateral hypothalamus on the turnover of monoamines in the terminal structures of the mesocorticolimbic and nigrostriatal systems: the nucleus accumbens (NAc) and striatum (St). The Wistar male rats were implanted electrodes in the lateral hypothalamus and further trained in self-stimulation test. Animals were also selected on aversive emotional reactions were observed after pressing the pedal for self-stimulation. Subsequently, forced stimulation was performed for 5 minutes and the animals were decapitated. The content of norepinephrine, dopamine (DA) and its metabolites 3,4-dioxiphenylacetic acid (DOPАС) and homovanilinic acid, serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in the nucleus accumbens and striatum were determined by high performance liquid chromatography with electrochemical detection. Positive and aversive stimulation of lateral hypothalamus decreased the level of DA in the NAc, however, only stimulation of the positive emotiogenic zone increased the DA and 5-HT turnover in the NAc, as evidenced by an increase in the DOPАС/DA and 5-HIAA/SER ratios, respectively. Rewarding and aversive stimulation decreased the level of 5-HT in St, however, only rewarding stimulation decreased the St level of 5-HIAA compared to control and animals with aversive stimulation. Rewarding stimulation increased the turnover of serotonin in St, as evidenced by the increase of 5-HIAA/5-HT ratios. The activity of the noradrenergic system did not change after rewarding and aversive stimulation. Thus, both rewarding and aversive electrical stimulation increases the turnover of DA and 5-HT in NAc and St. However, these changes are more significant after rewarding stimulation. DA turnover increases more in NAc, and 5-HT turnover in St. The data obtained indicate the specificity of the dopaminergic and serotonergic involvement for the formation of a modality of emotional reactions. Data may provide guidance for developing treatment strategies for neuropsychiatric diseases related to the malfunction of the reward system.

Control of food approach and eating by a GABAergic projection from lateral hypothalamus to dorsal pons

Electrical or optogenetic stimulation of lateral hypothalamic (LH) GABA neurons induces rapid vigorous eating in sated animals. The dopamine system has been implicated in the regulation of feeding. Previous work has suggested that a subset of LH GABA neurons projects to the ventral tegmental area (VTA) and targets GABA neurons, inhibiting them and thereby disinhibiting dopaminergic activity and release. Furthermore, stimulation-induced eating is attenuated by dopamine lesions or receptor antagonists. Here we explored the involvement of dopamine in LH stimulation-induced eating. LH stimulation caused sated mice to pick up pellets of standard chow with latencies that varied based on stimulation intensity; once food was picked up, animals ate for the remainder of the 60-s stimulation period. However, lesion of VTA GABA neurons failed to disrupt this effect. Moreover, direct stimulation of VTA or substantia nigra dopamine cell bodies failed to induce food approach or eating. Looking further, we found that some LH GABA fibers pass through the VTA to more caudal sites, where they synapse onto neurons near the locus coeruleus (LC). Similar eating was induced by stimulation of LH GABA terminals or GABA cell bodies in this peri-LC region. Lesion of peri-LC GABA neurons blocked LH stimulation-induced eating, establishing them as a critical downstream circuit element for LH neurons. Surprisingly, lesions did not alter body weight, suggesting that this system is not involved in the hunger or satiety mechanisms that govern normal feeding. Thus, we present a characterization of brain circuitry that may promote overeating and contribute to obesity.

The orexinergic neural pathway from the lateral hypothalamus to the nucleus accumbens and its regulation of palatable food intake

ObjectiveTo explore the orexinergic pathway from the lateral hypothalamus (LHA) to the nucleus accumbens (NAc) and its regulation on the palatable food intake. MethodsFluorescent gold retrograde tracing combined with fluoro-immunohistochemical staining were used to observe the projection of orexinergic neurons from LHA to NAc. The orexin-A expression in LHA and c-Fos in NAc were studied after electrical stimulation of LHA. The firing rates of neurons were monitored by single-unit extracellular electric discharge recording and the palatable food intake were measured after orexin microinjection in NAc or electrical stimulation of LHA. Results(1) Fluorescent gold retrograde tracing combined with fluoro-immunohistochemical staining showed some orexinergic neural projection from the LHA to the NAc shell. (2) Electrical stimulation of LHA significantly enhanced the expression of orexin-A in LHA and the expression of c-Fos in NAc (P < .05). (3) The results of single-unit extracellular discharge recording showed that the microinjection of orexin in NAc or electrical stimulation of LHA significantly increased the discharge activity of gastric distension responsive neurons in NAc, and the effect could be partly blocked by pretreatment of orexin-A receptor inhibitor SB334867 in NAc (P < .05). (4) Microinjection orexin-A in NAc or electrical stimulation of LHA significantly increased the palatable food intake in rats, and the effect also was partly inhibited by pretreatment of SB334867 in NAc (P < .05). ConclusionThere is an orexinergic pathway from LHA to NAc, which may have potential regulatory effects on food reward and obesity.

Optogenetic mapping of feeding and self-stimulation within the lateral hypothalamus of the rat.

The lateral hypothalamus (LH) includes several anatomical subregions involved in eating and reward motivation. This study explored localization of function across different LH subregions in controlling food intake stimulated by optogenetic channelrhodopsin excitation, and in supporting laser self-stimulation. We particularly compared the tuberal LH subregion, the posterior LH subregion, and the lateral preoptic area. Local diameters of tissue optogenetically stimulated within the LH were assessed by measuring laser-induced Fos plumes and Jun plumes via immunofluorescence surrounding optic fiber tips. Those plume diameters were used to map localization of function for behavioral effects elicited by LH optogenetic stimulation. Optogenetic stimulation of the tuberal subsection of the LH produced the most robust eating behavior and food intake initially, but produced only mild laser self-stimulation in the same rats. However, after repeated exposures to optogenetic stimulation, tuberal LH behavioral profiles shifted toward more self-stimulation and less food intake. By contrast, stimulation of the lateral preoptic area produced relatively little food intake or self-stimulation, either initially or after extended stimulation experience. Stimulation in the posterior LH subregion supported moderate self-stimulation, but not food intake, and at higher laser intensity shifted valence to evoke escape behaviors. We conclude that the tuberal LH subregion may best mediate stimulation-bound increases in food intake stimulated by optogenetic excitation. However, incentive motivational effects of tuberal LH stimulation may shift toward self-stimulation behavior after repeated stimulation. By contrast, the lateral preoptic area and posterior LH do not as readily elicit either eating behavior or laser self-stimulation, and may be more prone to higher-intensity aversive effects.

Chemical stimulation of the lateral hypothalamus induces antiallodynic and anti-thermal hyperalgesic effects in animal model of neuropathic pain: Involvement of orexin receptors in the spinal cord

To date several circuities in supraspinal site of the central nervous system have been known to engage in pain modulation. Lateral hypothalamus (LH) is known as part of the circuit of pain modulation among supraspinal sites. Its role in several animal pain models has been well defined. In this study, we examined the role of spinal orexin receptors in antinociceptive response elicited by the LH stimulation in an animal model of neuropathic pain. Male Wistar rats were unilaterally implanted with a cannula into the LH and a catheter into the L4-L5 segments of the spinal cord followed by chronic constriction injury (CCI) surgery. Intra-LH microinjection of carbachol (500 nM; 0.5 μL) was done 5 min after intrathecal administration of the orexin receptor antagonists, SB-334867 or TCS OX2 29; control animals received DMSO. Mechanical allodynia and thermal hyperalgesia were evaluated using von Frey filaments and a thermal stimulus. The results showed that carbachol induces antiallodynic and anti-thermal hyperalgesic effects in a dose-dependent manner. The antiallodynic and anti-thermal hyperalgesic effects induced by intra-LH injection of carbachol were reversed by intrathecal administration of 10 μL–100 nM solutions of SB-334867 or TCS OX2 in neuropathic rats. However, solely intrathecal administration of both antagonists had no effect in neuropathic rats. There appears to be a neural pathway from the LH to the spinal cord, which potentially contributes to the modulation of neuropathic pain. The implications are that there may be novel therapeutic approaches for the treatment of people suffered from chronic neuropathic pain in clinic.

Involvement of Orexinergic System Within the Nucleus Accumbens in Pain Modulatory Role of the Lateral Hypothalamus in Orofacial Pain Model

Lateral hypothalamus (LH) contains a large population of orexinergic neurons. Many studies have investigated the function of these neurons and it is clear that they are involved in pain modulation. The nucleus accumbens (NAc) receives many orexinergic projections, and accumbal neurons express both receptors of orexin (OX1R and OX2R). In this study, we investigated the role of accumbal orexinergic receptors in the LH-induced antinociception during formalin-induced orofacial pain. Male adult Wistar rats weighing 230-250 g were used in this study. Cannulae were unilaterally implanted in their skull for microinjections. SB334867 (OX1 receptor antagonist) or TCS OX2 29 (OX2 receptor antagonist) at the doses of 3, 10 and 30 nM were injected into the NAc with/without intra-LH microinjection of carbachol (250 nM/rat). Carbachol was used for chemical stimulation of orexinergic neurons in the LH. Our results showed that intra-LH carbachol following injection of formalin into animals' upper lip reduced nociception in both phases of formalin test. SB334867 and TCS OX2 29 were able to reduce LH-induced antinociception in both phases. Although the highest dose of SB334867 and TCS OX2 29 (30 nM) was effective in both phases, the TCS OX2 29 but not SB334867 at the dose of 10 nM could not reduce the antinociceptive responses induced by LH stimulation during the first (early) phase. It suggests that contribution of accumbal orexinergic receptors in the first phase of formalin test is more than the second (late) phase, and these results provide further evidence for the involvement of orexinergic system in the modulation of inflammatory orofacial pain.

Pain condition and sex differences in the descending noradrenergic system following lateral hypothalamic stimulation

The lateral hypothalamus (LH) is known to modulate nociception via the descending noradrenergic system in acute nociception, but less is known about its role in neuropathic pain states. In naïve females, LH stimulation produces opposing effects of α-adrenoceptors, with α2-adrenoceptors mediating antinociception, while pronociceptive α1-adrenoceptors attenuate the effect. Whether this opposing response is seen in neuropathic conditions or in naïve males is unknown. We used a mixed factorial design to compare male and female rats with chronic constriction injury (CCI) to naïve rats, measured by Total Paw Withdrawal (TPW) responses to a thermal stimulus. Rats received one of three doses of carbachol to stimulate the LH followed by intrathecal injection of either an α1- or an α2-adrenoceptor antagonist (WB4101 or yohimbine, resp.) or saline for control. Overall, naïve rats showed a more pronounced opposing alpha-adrenergic response than CCI rats (p<0.04). Naïve male and female rats demonstrated antinociception following α1-adrenoceptor blockade and hyperalgesia following α2-adrenoceptor blockade. Male CCI rats also showed dose dependent effects from either WB4101 or yohimbine (p<0.05), while female CCI rats had significant antinociception from WB4101 (p<0.05), but no effect from yohimbine. These results support the idea that peripheral nerve damage differentially alters the descending noradrenergic modulatory system in male and female rats, and notably, that female CCI rats do not show antinociception from descending noradrenergic input. These findings are suggestive that clinical therapies that recruit the descending noradrenergic system may require a different approach based on patient gender.

Assessment of safety and outcome of lateral hypothalamic deep brain stimulation for obesity in a small series of patients with Prader-Willi syndrome

The authors describe a small case series of four patients, age range 18–28 years, with Prader-Willi syndrome and obesity. All had received childhood growth hormone therapy, two had previous bariatric surgery, and all had psychiatric comorbidities before the current intervention. All received deep brain stimulation, via electrodes bilaterally implanted in the lateral hypothalamic area, over a 6-month protocol. The intervention was ineffective in reducing body weight or BMI, which actually increased by on average 9.6% and 5.8%, respectively.

Role of orexin receptors within the dentate gyrus of the hippocampus in antinociception induced by chemical stimulation of the lateral hypothalamus in the tail-flick test as a model of acute pain in rats

The dentate gyrus (DG) as a part of the hippocampal formation is considered one of the brain areas involved in pain perception. The orexin neurons in the lateral hypothalamus (LH) also show connections to regions engaged in the circuitry of pain modulation and many studies have shown their potential to alter pain transmission through the nervous system. However, the role of orexin receptors (OXRs) of the DG in mediation of antinociceptive responses induced by the LH stimulation in rats has not yet been investigated. Hence, the present study was an attempt to examine the role of OXRs located within the DG in the pain modulation induced by chemical stimulation of the LH. Adult male Wistar rats weighing 220–250 g were unilaterally implanted with two separate cannulae into the LH and DG. Intra-DG administration of the orexin-1 receptor (OX1R) antagonist, SB334867 or the orexin-2 receptor (OX2R) antagonist, TCS OX2 29 was performed just 5 min before intra-LH carbachol microinjection. Antinociceptive effects were measured using the tail-flick apparatus. The results showed that OX1R and OX2R antagonists dose-dependently decreased the antinociceptive effect of carbachol. In addition, the effective dose of SB334867 was lesser than that of TCS OX2 29, which indicates the more prominent role of OX1R of the DG in carbachol-induced antinociception. None of the antagonists had any significant effect when administrated without intra-LH carbachol microinjection. It seems to be a neural circuit includes the LH and DG, which plays a major role in the neural basis of pain modulation.

Assessment of Safety and Outcome of Lateral Hypothalamic Deep Brain Stimulation for Obesity in a Small Series of Patients With Prader-Willi Syndrome

Deep brain stimulation (DBS) has been investigated for treatment of morbid obesity with variable results. Patients with Prader-Willi syndrome (PWS) present with obesity that is often difficult to treat. To test the safety and study the outcome of DBS in patients with PWS. This case series was conducted in the Hospital das Clínicas, University of São Paulo, Brazil. Four patients with genetically confirmed PWS presenting with severe obesity were included. Deep brain stimulation electrodes were bilaterally implanted in the lateral hypothalamic area. After DBS implantation, the treatment included the following phases: titration (1-2 months), stimulation off (2 months), low-frequency DBS (40 Hz; 1 month), washout (15 days), high-frequency DBS (130 Hz; 1 month), and long-term follow-up (6 months). Primary outcome measures were adverse events recorded during stimulation and long-term DBS treatment. Secondary outcomes consisted of changes in anthropometric measures (weight, body mass index [calculated as weight in kilograms divided by height in meters squared], and abdominal and neck circumference), bioimpedanciometry, and calorimetry after 6 months of treatment compared with baseline. The following evaluations and measurements were conducted before and after DBS: clinical, neurological, psychiatric, neuropsychological, anthropometry, calorimetry, blood workup, hormonal levels, and sleep studies. Adverse effects were monitored during all follow-up visits. Four patients with PWS were included (2 male and 2 female; ages 18-28 years). Baseline mean (SD) body mass index was 39.6 (11.1). Two patients had previous bariatric surgery, and all presented with psychiatric comorbidity, which was well controlled with the use of medications. At 6 months after long-term DBS, patients had a mean 9.6% increase in weight, 5.8% increase in body mass index, 8.4% increase in abdominal circumference, 4.2% increase in neck circumference, 5.3% increase in the percentage of body fat, and 0% change in calorimetry compared with baseline. Also unchanged were hormonal levels and results of blood workup, sleep studies, and neuropsychological evaluations. Two patients developed stimulation-induced manic symptoms. Discontinuation of DBS controlled this symptom in 1 patient. The other required adjustments in medication dosage. Two infections were documented, 1 associated with skin picking. Safety of lateral hypothalamic area stimulation was in the range of that demonstrated in patients with similar psychiatric conditions receiving DBS. In the small cohort of patients with PWS treated in our study, DBS was largely ineffective.

Effects of intrathecal administration of orexin-1 receptor antagonist on antinociceptive responses induced by chemical stimulation of lateral hypothalamus in an animal model of tonic nociception

Orexins are produced in the restricted regions of the lateral hypothalamus (LH). However, orexinergic receptors and projections are localized in wide regions like nucleus accumbens, ventral tegmental area, periaqueductal gray area and spinal cord which are involved in the pain modulation. This study was carried out to investigate the effects of intrathecal administration of orexin-1 receptor antagonist (SB-334867) in the spinal antinociception induced by intra-LH administration of carbachol (cholinergic receptor agonist) in both early and late phases of pain related behaviors in formalin test. In this study, pain-related behaviors (pain scores) were evaluated using the formalin test during 5-min block intervals for a 60-min period in seventy male Wistar rats were given SB-334867 (3, 10, 30 and 100 μM/10 μl) or vehicle (DMSO 12%; 10 μl) intrathecally following intra-LH administration of carbachol (250 nM/rat). Our data showed that intra-LH injection of carbachol attenuated the formalin-induced biphasic pain responses, and intrathecal administration of SB-334867 dose-dependently decreased LH stimulation-induced antinociceptive responses during both phases. Moreover, administration of different doses of SB-334867 during the early phase were more effective than those during the late phase. The antinociceptive role of orexinergic system in the formalin test through a neural pathway from the LH to the spinal cord provides evidence that orexins can be useful in therapeutic targets for pain relief.

Role of D1- and D2-like dopaminergic receptors in the nucleus accumbens in modulation of formalin-induced orofacial pain: Involvement of lateral hypothalamus

The role of dopaminergic system in modulation of formalin-induced orofacial nociception has been established. The present study aims to investigate the role of dopaminergic receptors in the nucleus accumbens (NAc) in modulation of nociceptive responses induced by formalin injection in the orofacial region. One hundred and six male Wistar rats were unilaterally implanted with two cannulae into the lateral hypothalamus (LH) and NAc. Intra-LH microinjection of carbachol, a cholinergic receptor agonist, was done 5min after intra-accumbal administration of different doses of SCH23390 (D1-like receptor antagonist) or sulpiride (D2-like receptor antagonist). After 5min, 50μl of 1% formalin was subcutaneously injected into the upper lip for inducing the orofacial pain. Carbachol alone dose-dependently reduced both phases of the formalin-induced orofacial pain. Intra-accumbal administration of SCH23390 (0.25, 1 and 4μg/0.5μl saline) or sulpiride (0.25, 1 and 4μg/0.5μl DMSO) before LH stimulation by carbachol (250nM/0.5μl saline) antagonized the antinociceptive responses during both phases of orofacial formalin test. The effects of D1- and D2-like receptor antagonism on the LH stimulation-induced antinociception were almost similar during the early phase. However, compared to D1-like receptor antagonism, D2-like receptor antagonism was a little more effective but not significant, at blocking the LH stimulation-induced antinociception during the late phase of formalin test. The findings revealed that there is a direct or indirect neural pathway from the LH to the NAc which is at least partially contributed to the modulation of formalin-induced orofacial nociception through recruitment of both dopaminergic receptors in this region.

A neural basis for antagonistic control of feeding and compulsive behaviors

Abnormal feeding often co-exists with compulsive behaviors, but the underlying neural basis remains unknown. Excessive self-grooming in rodents is associated with compulsivity. Here, we show that optogenetically manipulating the activity of lateral hypothalamus (LH) projections targeting the paraventricular hypothalamus (PVH) differentially promotes either feeding or repetitive self-grooming. Whereas selective activation of GABAergic LH→PVH inputs induces feeding, activation of glutamatergic inputs promotes self-grooming. Strikingly, targeted stimulation of GABAergic LH→PVH leads to rapid and reversible transitions to feeding from induced intense self-grooming, while activating glutamatergic LH→PVH or PVH neurons causes rapid and reversible transitions to self-grooming from voracious feeding induced by fasting. Further, specific inhibition of either LH→PVH GABAergic action or PVH neurons reduces self-grooming induced by stress. Thus, we have uncovered a parallel LH→PVH projection circuit for antagonistic control of feeding and self-grooming through dynamic modulation of PVH neuron activity, revealing a common neural pathway that underlies feeding and compulsive behaviors.