Nociceptive stimuli activate the hypothalamus-habenula circuit to inhibit the mesolimbic reward system

Nociceptive signals interact with various regions of the brain, including those involved in physical sensation, reward, cognition, and emotion. Emerging evidence points to a role of nociception in the modulation of the mesolimbic reward system. The mechanism by which nociception affects dopamine (DA) signaling and reward is unclear. The lateral hypothalamus (LH) and the lateral habenula (LHb) receive somatosensory inputs and are structurally connected with the mesolimbic DA system. Here we show that the LH-LHb pathway is necessary for nociceptive modulation of this system. Our extracellular single-unit recordings and head-mounted microendoscopic calcium imaging revealed that nociceptive stimulation by tail-pinch excited LHb and LH neurons, which was inhibited by chemical lesion of the LH. Tail-pinch decreased extracellular DA release in the nucleus accumbens ventrolateral shell, which was blocked by disruption of the LH. Furthermore, tail-pinch attenuated cocaine-induced locomotor activity, 50-kHz ultrasonic vocalizations and reinstatement of cocaine-seeking behavior, which was inhibited by chemogenetic silencing of the LH-LHb pathway. Our findings suggest that nociceptive stimulation recruits the LH-LHb pathway to inhibit mesolimbic DA system and drug reinstatement.

Delineating neural responses and functional connectivity changes during vestibular and nociceptive stimulation reveal the uniqueness of cortical vestibular processing

Vestibular information is ubiquitous and often processed jointly with visual, somatosensory and proprioceptive information. Among the cortical brain regions associated with human vestibular processing, area OP2 in the parietal operculum has been proposed as vestibular core region. However, delineating responses uniquely to vestibular stimulation in this region using neuroimaging is challenging for several reasons: First, the parietal operculum is a cytoarchitectonically heterogeneous region responding to multisensory stimulation. Second, artificial vestibular stimulation evokes confounding somatosensory and nociceptive responses blurring responses contributing to vestibular perception. Furthermore, immediate effects of vestibular stimulation on the organization of functional networks have not been investigated in detail yet. Using high resolution neuroimaging in a task-based and functional connectivity approach, we compared two equally salient stimuli—unilateral galvanic vestibular (GVS) and galvanic nociceptive stimulation (GNS)—to disentangle the processing of both modalities in the parietal operculum and characterize their effects on functional network architecture. GNS and GVS gave joint responses in area OP1, 3, 4, and the anterior and middle insula, but not in area OP2. GVS gave stronger responses in the parietal operculum just adjacent to OP3 and OP4, whereas GNS evoked stronger responses in area OP1, 3 and 4. Our results underline the importance of considering this common pathway when interpreting vestibular neuroimaging experiments and underpin the role of area OP2 in central vestibular processing. Global network changes were found during GNS, but not during GVS. This lack of network reconfiguration despite the saliency of GVS may reflect the continuous processing of vestibular information in the awake human.

Delineating Neural Responses and Functional Connectivity Changes During Vestibular and Nociceptive Stimulation Reveal the Uniqueness of Cortical Vestibular Processing

Vestibular information is ubiquitous and often processed jointly with visual, somatosensory and proprioceptive information. Among the cortical brain regions associated with human vestibular processing, area OP2 in the parietal operculum has been proposed as vestibular core region. However, delineating responses uniquely to vestibular stimulation in this region using neuroimaging is challenging for several reasons: Firstly, the parietal operculum is a cytoarchitectonically heterogeneous region responding to multisensory stimulation. Secondly, artificial vestibular stimulation evokes confounding somatosensory and nociceptive responses blurring responses contributing to vestibular perception. Furthermore, immediate effects of vestibular stimulation on the organization of functional networks have not been investigated in detail yet.Here, we compared two equally salient stimuli - galvanic vestibular stimulation (GVS) and galvanic nociceptive stimulation (GNS)- to disentangle the processing of both modalities in the parietal operculum and characterize their effects on functional network architecture. GNS and GVS gave joint responses in area OP1,3,4, and the anterior and middle insula, but not in area OP2. Contrasting both stimulation modalities resulted in stronger responses in parts of the parietal operculum adjacent to OP3 and OP4 during GVS, whereas GNS evoked stronger responses in area OP1,3 and 4. Our results underline the importance of considering this common multisensory trunk when interpreting vestibular neuroimaging experiments and further underpin the role of area OP2 in central vestibular processing. Global network changes were found during GNS, but not during GVS. This lack of network reconfiguration despite the saliency of GVS may reflect the continuous processing of vestibular information in the awake human.

A Multisensory fMRI Investigation of Nociceptive-Preferential Cortical Regions and Responses

The existence of nociceptive-specific brain regions has been a controversial issue for decades. Multisensory fMRI studies, which examine fMRI activities in response to various types of sensory stimulation, could help identify nociceptive-specific brain regions, but previous studies are limited by sample size and they did not differentiate nociceptive-specific regions and nociceptive-preferential regions, which have significantly larger responses to nociceptive input. In this study, we conducted a multisensory fMRI experiment on 80 healthy participants, with the aim to determine whether there are certain brain regions that specifically or preferentially respond to nociceptive stimulation. By comparing the evoked fMRI responses across four sensory modalities, we found a series of brain regions specifically or preferentially involved in nociceptive sensory input. Particularly, we found different parts of some cortical regions, such as insula and cingulate gyrus, play different functional roles in the processing of nociceptive stimulation. Hence, this multisensory study improves our understanding of the functional integrations and segregations of the nociceptive-related regions.

Parabrachial nucleus circuit governs neuropathic pain-like behavior

The lateral parabrachial nucleus (LPBN) is known to relay noxious information to the amygdala for processing affective responses. However, it is unclear whether the LPBN actively processes neuropathic pain characterized by persistent hyperalgesia with aversive emotional responses. Here we report that neuropathic pain-like hypersensitivity induced by common peroneal nerve (CPN) ligation increases nociceptive stimulation-induced responses in glutamatergic LPBN neurons. Optogenetic activation of GABAergic LPBN neurons does not affect basal nociception, but alleviates neuropathic pain-like behavior. Optogenetic activation of glutamatergic or inhibition of GABAergic LPBN neurons induces neuropathic pain-like behavior in naïve mice. Inhibition of glutamatergic LPBN neurons alleviates both basal nociception and neuropathic pain-like hypersensitivity. Repetitive pharmacogenetic activation of glutamatergic or GABAergic LPBN neurons respectively mimics or prevents the development of CPN ligation-induced neuropathic pain-like hypersensitivity. These findings indicate that a delicate balance between excitatory and inhibitory LPBN neuronal activity governs the development and maintenance of neuropathic pain.

Effects of isoflurane, remifentanil and dexmedetomidine on selected EEG parameters derived from a Narcotrend Monitor before and after nociceptive stimulation at different MAC multiples in cats

Background The aim of this prospective and complete cross-over study was to evaluate the effects of isoflurane, remifentanil and dexmedetomidine on EEG parameters derived from the Narcotrend® Monitor before and after nociceptive stimulation at different isoflurane MAC (minimal alveolar concentration) multiples. Seven adult European Domestic Short Hair cats were used. Each cat went through 3 experimental treatments. Group I received isoflurane, group IR received isoflurane and a constant rate infusion (CRI) of remifentanil (18 μg/kg/h IV), and group ID received isoflurane and a CRI of dexmedetomidine (3 μg/kg/h IV). The isoflurane MAC in each group was determined via supramaximal electrical stimulation. The EEG parameters were derived by a Narcotrend Monitor at specific time points before and after nociceptive stimulation at 0.75, 1.0 and 1.5 MAC. The depth of anaesthesia was also assessed by a clinical score. Results The mean MAC sparing effects in group IR and group ID were 9.8 and 55.2%, respectively. The best correlation of EEG and MAC multiples was found for the Narcotrend Index (NI) in group I (r = − 0.67). The NI was also able to differentiate between 0.75 MAC and 1.5 MAC in group IR. Spectral edge frequency had a lower correlation with MAC multiples in group I (r = − 0.62) but was able to differentiate between 0.75 MAC and 1.5 MAC in groups I and IR, and between 1.0 MAC and 1.5 MAC in group IR. Narcotrend Index, SEF 95 and MF increased significantly after nociceptive stimulation at 1.0 MAC in group I, and SEF 95 increased significantly at 0.75 MAC in group ID. The clinical score correlated closer than any of the EEG parameters with MAC in all groups, with highest correlation values in group I (r = − 0.89). Noxious stimulation led to a significant increase of the clinical score at 0.75 MAC and 1.0 MAC in group I. Conclusions The EEG parameters derived from the Narcotrend Monitor show correlation to isoflurane MAC multiples in cats, but the anaesthetic protocol and especially the addition of dexmedetomidine have great influence on the reliability. The Narcotrend Monitor can be used as an additional tool to assess anesthetic depth in cats.