Beneficial Effects of Ginger Root Extract on Pain Behaviors, Inflammation, and Mitochondrial Function in the Colon and Different Brain Regions of Male and Female Neuropathic Rats: A Gut-Brain Axis Study.

Background: Neuroinflammation and mitochondrial dysfunction have been implicated in the progression of neuropathic pain (NP) but can be mitigated by supplementation with gingerol-enriched ginger (GEG). However, the exact benefits of GEG for each sex in treating neuroinflammation and mitochondrial homeostasis in different brain regions and the colon remain to be determined.

Objective: Evaluate the effects of GEG on emotional/affective pain and spontaneous pain behaviors, neuroinflammation, as well as mitochondria homeostasis in the amygdala, frontal cortex, hippocampus, and colon of male and female rats in the spinal nerve ligation (SNL) NP model.

Cells and circuits for amygdala neuroplasticity in the transition to chronic pain.

Maladaptive plasticity is linked to the chronification of diseases such as pain, but the transition from acute to chronic pain is not well understood mechanistically. Neuroplasticity in the central nucleus of the amygdala (CeA) has emerged as a mechanism for sensory and emotional-affective aspects of injury-induced pain, although evidence comes from studies conducted almost exclusively in acute pain conditions and agnostic to cell type specificity. Here, we report time-dependent changes in genetically distinct and projection-specific CeA neurons in neuropathic pain.

Dysfunction of Small-Conductance Ca-Activated Potassium (SK) Channels Drives Amygdala Hyperexcitability and Neuropathic Pain Behaviors: Involvement of Epigenetic Mechanisms.

Neuroplasticity in the amygdala and its central nucleus (CeA) is linked to pain modulation and pain behaviors, but cellular mechanisms are not well understood. Here, we addressed the role of small-conductance Ca-activated potassium (SK) channels in pain-related amygdala plasticity. The facilitatory effects of the intra-CeA application of an SK channel blocker (apamin) on the pain behaviors of control rats were lost in a neuropathic pain model, whereas an SK channel activator (NS309) inhibited pain behaviors in neuropathic rats but not in sham controls, suggesting the loss of the inhibitory behavioral effects of amygdala SK channels.

Ginger Polyphenols Reverse Molecular Signature of Amygdala Neuroimmune Signaling and Modulate Microbiome in Male Rats with Neuropathic Pain: Evidence for Microbiota-Gut-Brain Axis.

Emerging evidence shows that the gut microbiota plays an important role in neuropathic pain (NP) via the gut-brain axis. Male rats were divided into sham, spinal nerve ligation (SNL), SNL + 200 mg GEG/kg BW (GEG200), and SNL + 600 mg GEG/kg BW (GEG600) for 5 weeks. The dosages of 200 and 600 mg GEG/kg BW for rats correspond to 45 g and 135 g raw ginger for human daily consumption, respectively.

Turmeric Bioactive Compounds Alleviate Spinal Nerve Ligation-Induced Neuropathic Pain by Suppressing Glial Activation and Improving Mitochondrial Function in Spinal Cord and Amygdala.

This study examined the effects of turmeric bioactive compounds, curcumin C3 complex® (CUR) and bisdemethoxycurcumin (BDMC), on mechanical hypersensitivity and the gene expression of markers for glial activation, mitochondrial function, and oxidative stress in the spinal cord and amygdala of rats with neuropathic pain (NP). Twenty-four animals were randomly assigned to four groups: sham, spinal nerve ligation (SNL, an NP model), SNL+100 mg CUR/kg BW p.o.

Pain-related cortico-limbic plasticity and opioid signaling.

Neuroplasticity in cortico-limbic circuits has been implicated in pain persistence and pain modulation in clinical and preclinical studies. The amygdala has emerged as a key player in the emotional-affective dimension of pain and pain modulation. Reciprocal interactions with medial prefrontal cortical regions undergo changes in pain conditions.

Gingerol-Enriched Ginger Supplementation Mitigates Neuropathic Pain Mitigating Intestinal Permeability and Neuroinflammation: Gut-Brain Connection.

Emerging evidence suggests an important role of the gut-brain axis in the development of neuropathic pain (NP). We investigated the effects of gingerol-enriched ginger (GEG) on pain behaviors, as well as mRNA expressions of inflammation tight junction proteins in GI tissues (colon) and brain tissues (amygdala, both left and right) in animals with NP. Seventeen male rats were randomly divided into three groups: Sham, spinal nerve ligation (SNL, pain model), and SNL+0.

Kappa Opioid Receptor Blockade in the Amygdala Mitigates Pain Like-Behaviors by Inhibiting Corticotropin Releasing Factor Neurons in a Rat Model of Functional Pain.

Functional pain syndromes (FPS) occur in the absence of identifiable tissue injury or noxious events and include conditions such as migraine, fibromyalgia, and others. Stressors are very common triggers of pain attacks in various FPS conditions. It has been recently demonstrated that kappa opioid receptors (KOR) in the central nucleus of amygdala (CeA) contribute to FPS conditions, but underlying mechanisms remain unclear.

Optogenetic manipulations of CeA-CRF neurons modulate pain- and anxiety-like behaviors in neuropathic pain and control rats.

The amygdala plays a critical role in the emotional-affective component of pain and pain modulation. The central nucleus of amygdala (CeA) serves major output functions and has been linked to pain-related behaviors. Corticotropin releasing factor (CRF) in the CeA has emerged as an important modulator of pain and affective disorders.

Kappa opioid receptor activation in the amygdala disinhibits CRF neurons to generate pain-like behaviors.

Recent evidence suggests that kappa opioid receptors (KOR) in limbic brain regions such as the amygdala contribute to pain conditions, but underlying mechanisms remain to be determined. The amygdala is an important player in averse-affective aspects of pain and pain modulation. The central nucleus (CeA) serves output functions through projection neurons that include corticotropin releasing factor (CRF) expressing neurons.

Kappa opioid signaling in the central nucleus of the amygdala promotes disinhibition and aversiveness of chronic neuropathic pain.

Chronic pain is associated with neuroplastic changes in the amygdala that may promote hyper-responsiveness to mechanical and thermal stimuli (allodynia and hyperalgesia) and/or enhance emotional and affective consequences of pain. Stress promotes dynorphin-mediated signaling at the kappa opioid receptor (KOR) in the amygdala and mechanical hypersensitivity in rodent models of functional pain. Here, we tested the hypothesis that KOR circuits in the central nucleus of the amygdala (CeA) undergo neuroplasticity in chronic neuropathic pain resulting in increased sensory and affective pain responses.

Fear extinction learning ability predicts neuropathic pain behaviors and amygdala activity in male rats.

Background The amygdala plays a key role in fear learning and extinction and has emerged as an important node of emotional-affective aspects of pain and pain modulation. Impaired fear extinction learning, which involves prefrontal cortical control of amygdala processing, has been linked to neuropsychiatric disorders. Here, we tested the hypothesis that fear extinction learning ability can predict the magnitude of neuropathic pain.

Small conductance calcium activated potassium (SK) channel dependent and independent effects of riluzole on neuropathic pain-related amygdala activity and behaviors in rats.

Background And Purpose: Chronic neuropathic pain is an important healthcare issue with significant emotional components. The amygdala is a brain region involved in pain and emotional-affective states and disorders. The central amygdala output nucleus (CeA) contains small-conductance calcium-activated potassium (SK) channels that can control neuronal activity.

Spontaneous activity does not predict morphological type in cerebellar interneurons.

The effort to determine morphological and anatomically defined neuronal characteristics from extracellularly recorded physiological signatures has been attempted with varying success in different brain areas. Recent studies have attempted such classification of cerebellar interneurons (CINs) based on statistical measures of spontaneous activity. Previously, such efforts in different brain areas have used supervised clustering methods based on standard parameterizations of spontaneous interspike interval (ISI) histograms.

Long-term climbing fibre activity induces transcription of microRNAs in cerebellar Purkinje cells.

Synaptic activation of central neurons is often evoked by electrical stimulation leading to post-tetanic potentiation, long-term potentiation or long-term depression. Even a brief electrical tetanus can induce changes in as many as 100 proteins. Since climbing fibre activity is often associated with cerebellar behavioural plasticity, we used horizontal optokinetic stimulation (HOKS) to naturally increase synaptic input to floccular Purkinje cells in mice for hours, not minutes, and investigated how this activity influenced the transcription of microRNAs, small non-coding nucleotides that reduce transcripts of multiple, complementary mRNAs.

Microlesions of the inferior olive reduce vestibular modulation of Purkinje cell complex and simple spikes in mouse cerebellum.

Cerebellar Purkinje cells have two distinct action potentials: complex spikes (CSs) are evoked by single climbing fibers that originate from the contralateral inferior olive. Simple spikes (SSs) are often ascribed to mossy fiber-granule cell-parallel fiber inputs to Purkinje cells. Although generally accepted, this view lacks experimental support.

Topsy turvy: functions of climbing and mossy fibers in the vestibulo-cerebellum.

The cerebellum's role in sensory-motor control and adaptation is undisputed. However, a key hypothesis pertaining to the function of cerebellar circuitry lacks experimental support. It is universally assumed that the discharge of mossy fibers accounts for modulation of Purkinje cell "simple spikes" (SSs).

Climbing fiber-evoked Purkinje cell discharge reduces expression of GABA(A) receptor-associated protein and decreases its interaction with GABA(A) receptors.

Sustained neuronal activity induces synaptic remodeling, in part, by altering gene expression. We have used a major climbing fiber pathway onto cerebellar Purkinje cells to investigate the effects of sustained climbing fiber-evoked glutamatergic synaptic transmission on transcription, expression and phosphorylation of proteins related to the regulation of inhibitory GABA(A) receptor function. Binocular horizontal optokinetic stimulation was used to modulate climbing fiber signals to Purkinje cells in the flocculus and nodulus of rabbits and mice.

Functions of interneurons in mouse cerebellum.

The output signal of Purkinje cells is conveyed by the modulated discharge of simple spikes (SSs) often ascribed to mossy fiber-granule cell-parallel fiber inputs to Purkinje cell dendrites. Although generally accepted, this view lacks experimental support. We can address this view by controlling afferent signals that reach the cerebellum over climbing and mossy fiber pathways.

Activity-dependent expression of acyl-coenzyme a-binding protein in retinal muller glial cells evoked by optokinetic stimulation.

Long-term horizontal optokinetic stimulation (HOKS) decreases the gain of the horizontal optokinetic reflex and evokes the second phase of optokinetic afternystagmus (OKAN-II). We investigated the possible molecular constituents of this adaptation. We used a differential display reverse transcriptase-PCR screen for mRNAs isolated from retinas of rabbits that received HOKS.

Cerebellar climbing fibers modulate simple spikes in Purkinje cells.

Purkinje cells have two action potentials: Climbing fiber responses (CFRs) and simple spikes (SSs). CFRs reflect the discharge of a single climbing fiber at multiple synaptic sites on the proximal dendrite of the Purkinje cell. SSs reflect the summed action of a subset of parallel fiber synapses on Purkinje cell dendritic spines.

Vestibularly evoked climbing-fiber responses modulate simple spikes in rabbit cerebellar Purkinje neurons.

The nodulus receives a primary vestibular afferent input from the ipsilateral labyrinth and a vestibularly related climbing-fiber input originating from the contralateral labyrinth. Previously we demonstrated that increased discharge of vestibularly evoked climbing-fiber responses (CFRs) in nodular Purkinje cells was correlated with decreased discharge of simple spikes (SSs). This left unresolved the question of whether vestibularly evoked antiphasic behavior of CFRs and SSs reflects a common neural mechanism or the activation of two separate parallel pathways.

Gabapentin and pregabalin suppress tactile allodynia and potentiate spinal cord stimulation in a model of neuropathy.

Spinal cord stimulation (SCS) is an effective tool in alleviating neuropathic pain. However, a number of well-selected patients fail to obtain satisfactory pain relief. Previous studies have demonstrated that i.