Sleep deprivation has been shown to exacerbate pain sensitivity and may contribute to the onset of chronic pain, yet the precise neural mechanisms underlying this association remain elusive. In our study, we explored the contribution of cholinergic neurons within the medial habenula (MHb) to hyperalgesia induced by sleep deprivation in rats. Our findings indicate that the activity of MHb cholinergic neurons diminishes during sleep deprivation and that chemogenetic stimulation of these neurons can mitigate the results. Interestingly, we did not find a direct response of MHb cholinergic neurons to pain stimulation. Further investigation identified the interpeduncular nucleus (IPN) and the paraventricular nucleus of the thalamus (PVT) as key players in the pro-nociceptive effect of sleep deprivation. Stimulating the pathways connecting the MHb to the IPN and PVT alleviated the hyperalgesia. These results underscore the important role of MHb cholinergic neurons in modulating pain sensitivity linked to sleep deprivation, highlighting potential neural targets for mitigating sleep deprivation-induced hyperalgesia.
Animals ; Habenula/physiology* ; Sleep Deprivation/physiopathology* ; Cholinergic Neurons/physiology* ; Male ; Hyperalgesia/physiopathology* ; Rats, Sprague-Dawley ; Rats ; Interpeduncular Nucleus/physiology* ; Pain Threshold/physiology* ; Midline Thalamic Nuclei/physiology* ; Neural Pathways/physiopathology*

The lateral habenula (LHb), which is a critical neuroanatomical hub and a regulator of midbrain monoaminergic centers, is activated by events resulting in negative valence and contributes to the expression of both appetitive and aversive behaviors. However, whole-brain cell-type-specific monosynaptic inputs to the LHb in both sexes remain incompletely elucidated. In this study, we used viral tracing combined with in situ hybridization targeting vesicular glutamate transporter 2 (vGlut2) and glutamic acid decarboxylase 2 (Gad2) to generate a comprehensive whole-brain atlas of inputs to glutamatergic and γ-aminobutyric acid (GABA)ergic neurons in the LHb. We found >30 ipsilateral and contralateral brain regions that projected to the LHb. Of these, there were significantly more monosynaptic LHb-projecting neurons from the lateral septum, anterior hypothalamus, dorsomedial hypothalamus, and ventromedial hypothalamus in females than in males. More interestingly, we found a stronger GABAergic projection from the medial septum to the LHb in males than in females. Our results reveal a comprehensive connectivity atlas of glutamatergic and GABAergic inputs to the LHb in both sexes, which may facilitate a better understanding of sexual dimorphism in physiological and pathological brain functions.
Animals ; Male ; Mice ; Glutamic Acid/metabolism* ; Habenula/metabolism* ; Hypothalamus/metabolism* ; Neural Pathways/physiology* ; Sex Characteristics ; Vesicular Glutamate Transport Protein 2/metabolism* ; Female

Animals ; Blood Pressure ; drug effects ; Electric Stimulation ; Female ; Habenula ; physiology ; Lidocaine ; pharmacology ; Male ; Raphe Nuclei ; physiology ; Rats ; Rats, Wistar ; Respiration ; drug effects ; Serotonin ; physiology

AIMTo investigate the effects and the possible mechanism of cocaine on the neurons of lateral habenular nucleus (LHb).

METHODSWe observed the effects on c-Fos protein expression in lateral habenular nucleus and medial habenular nucleus after injecting cocaine into a belly cavity and spontaneous and evoked discharge of pain-correlative unit through iontophoresis of cocaine into LHb. The delayed rectifier K+ current was recorded in the acute isolated LHb neuron in whole-cell mode.

RESULTS(1) The c-Fos protein expression was increased by cocaine treatment in LHb, but little effect in MHb. (2) Iontophoresis of cocaine into LHb increased the discharges of pain excitation unit and enhanced excitation response to noxious stimulation, but it decreased the discharges of pain inhibition unit and its responses to noxious stimulation in LHb. Cocaine inhibited the delayed rectifier K+ current.

CONCLUSIONCocaine can excite the LHb and increase its sensitivity. The probable mechanism is that cocaine inhibits the delayed rectifier K+ channels.

Animals ; Cocaine ; pharmacology ; Habenula ; drug effects ; metabolism ; physiology ; Proto-Oncogene Proteins c-fos ; metabolism ; Rats ; Rats, Wistar

Animals ; Cocaine ; pharmacology ; Habenula ; drug effects ; physiology ; Neurons ; drug effects ; physiology ; Pain Threshold ; drug effects ; Rats

AIMThe effect and possible mechanism of Melatonin (MEL) on firing rate of pain neurons in lateral habenular nucleus of rats were investigated in the experiment.

METHODSSingle extracellular firing were recorded to study the firing rate changes of pain neurons and sensitivity changes to pain stimulation induced by MEL in LHb of rats. Reverse effect of naloxone on the analgesia induced by melatonin was also observed.

RESULTSMelatonin showed the effects on the firing of pain neurons in the LHb and decreased the sensitivity of pain neurons to pain stimulation, which could be reversed by naloxone.

CONCLUSIONMelatonin can change the responses of pain neurons to pain stimulation via opioid receptor in the LHb, which might be one of analgesic mechanisms by MEL.

Analgesics ; pharmacology ; Animals ; Habenula ; drug effects ; physiology ; Male ; Melatonin ; pharmacology ; Neuralgia ; physiopathology ; Neurons ; drug effects ; physiology ; Rats ; Rats, Wistar

Animals ; Habenula ; cytology ; drug effects ; Male ; Microelectrodes ; Neurons ; drug effects ; physiology ; Pain ; Pregnanolone ; pharmacology ; Rats ; Rats, Wistar

AIMTo observe the responses of pain-related neurons in habenula to the nociceptive stimuli and classic analgesic morphine for inquiring into its characteristics of pain.

METHODSThe experiment was proceeded with adult rats under light anesthetized. Through the cannula inserted by operation or the multielectrode injecting the morphine, naloxone, CCK-8 and etc into lateral cerebro-ventricule or habenula, the unit firings from the neurons of habenula were recorded.

RESULTSThe unit firings were recorded from pain-related neurons distributed in MHb or LHb. The pain-related neurons could be differentiated into pain excitatory or pain inhibitory neurons. After the morphine iontophoresed, the main response of the pain excitatory neurons was inhibited, the pain inhibitory neurons were excited. The naloxone iontophoresed could antagonize the analgesic effect of morphine on neurons of habenula. After the morphine injected (10 mg/kg, i. p) into morphine-tolerated rats, the analgesic efficacy of pain-related neurons in LHb was more stronger than in MHb. It showed that the neurons in LHb were suffered from morphine was higher than MHb. After injection of antagonist of CCK-8 into lateral cerebro-ventricle, morphine injected peritoneally could weaken the tolerance level of morphine. Conversely, after injection of morphine (10 mg/kg, i. p.) 10 min, second time injection of CCK-8 (15 ng/10 microl) into lateral cerebro-ventricle could antagonize the analgesic action of morphine on the neurons in LHb, but in MHb the antagonized action was not obviously.

CONCLUSIONThe excitatory and inhibitory neurons in Hb were sensitive to the nociceptive stimuli and not easy to adapt to it. The sensitivity of the neurons in LHb to morphine was more higher than the neurons in MHb.

Animals ; Habenula ; cytology ; drug effects ; Morphine ; pharmacology ; Naloxone ; pharmacology ; Neurons ; drug effects ; physiology ; Pain Threshold ; drug effects ; Rats ; Rats, Wistar ; Sincalide ; pharmacology

AIMTo investigate whether if the Habenula is the main relay involved in the vasopressor effect induced by the stimulus of insular cortex, central-, lateral amygdaloid nucleus respectively.

METHODSElectrostimulation of the nuclei mention above respectively, and microinjection of lidocaine into Habenula unilaterally and bilaterally.

RESULTSWhen INS or CeA was stimulated, inducing an obvious increase of blood pressure. To stimulate INS or CeA after microinjecting lidocaine into Hb 5 minutes, the amplitudes of the vasopressor responses were decreased significantly, and the decrease of the bilaterally was larger (decreased value: 41.7% in INS, 46.1% in CeA) than that of unilaterally (decreased value: 36.9% in INS, 39.6% in CeA).

CONCLUSIONHabenula is one of the main relays involved in the vasopressor effects induced by the stimulus of insular cortex, central-, lateral amygdaloid nucleus.

Amygdala ; physiology ; Animals ; Blood Pressure ; physiology ; Cerebral Cortex ; physiology ; Electric Stimulation ; Habenula ; physiology ; Neural Pathways ; physiology ; Rats ; Rats, Wistar

AIMTo explore whether dorsomedial hypothalamic nucleus (DMH) is involved in the cardiovascular responses induced by habenular nucleus (Hb) stimulation and inhibitory effect of deep peroneal nerve (DPN) stimulation on above responses or not and to analysis transmitter mechanism.

METHODSExperiments were performed on white male rabbits anesthetised with chloralose and urethan. Experimental data were collected by means of stimulating Hb and DPN, recording arterial blood pressure and ectal electrocardiogram (EECG) and microinjecting transmitter blocker.

RESULTSProminent pressor and ischemic EECG segment changes were elicited by Hb stimulation (P < 0.01) Microinjecting kynurenic acid into ipsilateral DMH had partial blocking effect on pressor and ischemic EECG-ST segment changes induced by Hb stimulation (P < 0.01). Stimulation of bilateral DPN prominently inhibited the pressor and ischemic EECG-ST changes induced by Hb stimulation (P < 0.01, P < 0.05). Microinjecting naloxone into ipsilateral DMH decreased the inhibitory effect of DPN stimulation on above cardiovascular responses elicited by Hb stimulation (P < 0.01, P < 0.05).

CONCLUSIONGlutamic acid receptor in DMH is involved in pressor and ischemic changes induced by Hb stimulation. DMH and opiate peptide receptors in DMH are involved in the inhibitory effect of DPN stimulation on pressor and ischemic changes induced by Hb stimulation.

Animals ; Cardiovascular System ; Dorsomedial Hypothalamic Nucleus ; physiology ; Electric Stimulation ; Electrocardiography ; Habenula ; physiology ; Heart Rate ; Male ; Peroneal Nerve ; physiology ; Rabbits