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The Journal of Clinical Investigation Jun 2024We report that diazepam binding inhibitor (DBI) is a glial messenger mediating satellite glia-sensory neuron crosstalk in the dorsal root ganglion (DRG). DBI is highly...
We report that diazepam binding inhibitor (DBI) is a glial messenger mediating satellite glia-sensory neuron crosstalk in the dorsal root ganglion (DRG). DBI is highly expressed in satellite glia cells (SGCs) of mice, rat and human, but not in sensory neurons or most other DRG-resident cells. Knockdown of DBI results in a robust mechanical hypersensitivity without major effects on other sensory modalities. In vivo overexpression of DBI in SGCs reduces sensitivity to mechanical stimulation and alleviates mechanical allodynia in neuropathic and inflammatory pain models. We further show that DBI acts as an unconventional agonist and positive allosteric modulator at the neuronal GABAA receptors, particularly strongly effecting those with a high-affinity benzodiazepine binding site. Such receptors are selectively expressed by a subpopulation of mechanosensitive DRG neurons and these are also more enwrapped with DBI-expressing glia, as compared to other DRG neurons, suggesting a mechanism for specific effect of DBI on mechanosensation. These findings identified a new, peripheral neuron-glia communication mechanism modulating pain signalling, which can be targeted therapeutically.
PubMed: 38888973
DOI: 10.1172/JCI176227 -
The role of spinal neurons targeted by corticospinal neurons in central poststroke neuropathic pain.CNS Neuroscience & Therapeutics Jun 2024Central poststroke pain (CPSP) is one of the primary sequelae following stroke, yet its underlying mechanisms are poorly understood.
BACKGROUND
Central poststroke pain (CPSP) is one of the primary sequelae following stroke, yet its underlying mechanisms are poorly understood.
METHODS
By lesioning the lateral thalamic nuclei, we first established a CPSP model that exhibits mechanical and thermal hypersensitivity. Innocuous mechanical stimuli following the thalamic lesion evoked robust neural activation in somatosensory corticospinal neurons (CSNs), as well as in the deep dorsal horn, where low threshold mechanosensory afferents terminate. In this study, we used viral-based mapping and intersectional functional manipulations to decipher the role of somatosensory CSNs and their spinal targets in the CPSP pathophysiology.
RESULTS
We first mapped the post-synaptic spinal targets of lumbar innervating CSNs using an anterograde trans-synaptic AAV1-based strategy and showed these spinal interneurons were activated by innocuous tactile stimuli post-thalamic lesion. Functionally, tetanus toxin-based chronic inactivation of spinal neurons targeted by CSNs prevented the development of CPSP. Consistently, transient chemogenetic silencing of these neurons alleviated established mechanical pain hypersensitivity and innocuous tactile stimuli evoked aversion linked to the CPSP. In contrast, chemogenetic activation of these neurons was insufficient to induce robust mechanical allodynia typically observed in the CPSP.
CONCLUSION
The CSNs and their spinal targets are required but insufficient for the establishment of CPSP hypersensitivity. Our study provided novel insights into the neural mechanisms underlying CPSP and potential therapeutic interventions to treat refractory central neuropathic pain conditions.
Topics: Animals; Neuralgia; Pyramidal Tracts; Male; Stroke; Neurons; Hyperalgesia; Rats, Sprague-Dawley; Rats; Disease Models, Animal; Spinal Cord
PubMed: 38887838
DOI: 10.1111/cns.14813 -
Cureus May 2024Although research suggests that less than half of individuals who have surgical procedures report effective postoperative pain alleviation, the majority of patients... (Review)
Review
Although research suggests that less than half of individuals who have surgical procedures report effective postoperative pain alleviation, the majority of patients endure acute postoperative discomfort. To lessen and manage postoperative pain, a variety of preoperative, intraoperative, and postoperative treatments and management methods are available. For several years an opioid called buprenorphine has become an effective tool to treat opioid use disorder (OUD) in patients across many different demographics. It has however endured barriers to its usage which can be seen when treating patients with chronic pain or postoperative pain, who also have an OUD. While buprenorphine may be underutilized within the clinical setting, the significantly low rates of chronic abuse when using the drug allow it to be an attractive treatment option for patients. This paper aims to explore a wide range of studies that examine buprenorphine as an analgesic and how it can be used for preoperative pain and postoperative pain. This paper will give an in-depth analysis of buprenorphine and its use in patients with chronic pain as well as OUD. A systematic literature review was performed by identifying studies through the database PubMed. The data from various publications were gathered with preference being given to publications within the last three years. We reviewed studies that examined the pain level of the patients after having buprenorphine. Despite long-available pharmacologic evidence and clinical research, buprenorphine has maintained a mystique as an analgesic. Its usage in the treatment of OUD was further influenced by its well-known safety benefits and relative lack of psychomimetic side effects compared to other opioids. For patients accustomed to long-term, high-dose opioids who may be experiencing hyperalgesia but have not been informed about this phenomenon by their doctors or the potential for buprenorphine to resolve it, buprenorphine's pronounced antihyperalgesic effect is a compelling pharmacologic characteristic that makes it particularly attractive as an option. When used in pre-, peri-, and postoperative circumstances, buprenorphine provides various pain-management benefits and patients can still benefit from effective pain management from mu-opioid agonists while remaining on buprenorphine. Buprenorphine can be continued at a reduced dose as needed to avoid withdrawal symptoms and to improve the analgesic efficiency of mu-opioid agonists used in combination with acute postoperative pain in light of the evidence at hand. Buprenorphine administration needs a patient-centered, multidisciplinary strategy that considers the benefits and drawbacks of the many perioperative therapy options to have the best chance of success.
PubMed: 38883082
DOI: 10.7759/cureus.60341 -
Methods in Cell Biology 2024Neuropathic pain, defined as the most terrible of all tortures, which a nerve wound may inflict, is a common chronic painful condition caused by gradual damage or...
Neuropathic pain, defined as the most terrible of all tortures, which a nerve wound may inflict, is a common chronic painful condition caused by gradual damage or dysfunction of the somatosensory nervous system. As with many chronic diseases, neuropathic pain has a profound economic and emotional impact worldwide and represents a major public health issue from a treatment standpoint. This condition involves multiple sensory symptoms including impaired transmission and perception of noxious stimuli, burning, shooting, spontaneous pain, mechanical or thermal allodynia and hyperalgesia. Current pharmacological options for the treatment of neuropathic pain are limited, ineffective and have unacceptable side effects. In this framework, a deeper understanding of the pathophysiology and molecular mechanisms associated with neuropathic pain is key to the development of promising new therapeutical approaches. For this purpose, a plethora of experimental models that mimic common clinical features of human neuropathic pain have been characterized in rodents, with the spinal nerve ligation (SNL) model being one of the most widely used. In this chapter, we provide a detailed surgical procedure of the SNL model used to induce neuropathic pain in rats and mice. We further describe the behavioral approaches used for stimulus-evoked and spontaneous pain assessment in rodents. Finally, we demonstrate that our SNL model induces multiple pain behaviors in rats and mice.
Topics: Animals; Neuralgia; Spinal Nerves; Disease Models, Animal; Ligation; Rats; Mice; Hyperalgesia; Pain Measurement; Male
PubMed: 38880529
DOI: 10.1016/bs.mcb.2024.03.006 -
Journal of Oral Biosciences Jun 2024Chronic constriction injury (CCI) of the infraorbital nerve induces neuropathic pain, such as allodynia and hyperalgesia, in the orofacial area. However, the changes in...
OBJECTIVE
Chronic constriction injury (CCI) of the infraorbital nerve induces neuropathic pain, such as allodynia and hyperalgesia, in the orofacial area. However, the changes in the local circuits of the central nervous system following CCI remain unclear. This study aimed to identify the changes following CCI in Thy1-GCaMP6s transgenic mice.
METHODS
Neural activity in the primary somatosensory cortex (S1) and motor cortex (M1) following whisker stimulation was assessed using in vivo Ca imaging. CCI-induced changes in responses were analyzed.
RESULTS
Before CCI, whisker stimulation induced a greater Ca response in the contralateral S1 than in the ipsilateral S1 and contralateral M1. The peak Ca response amplitude in the bilateral S1 and contralateral M1 decreased two days after CCI compared to before CCI. Decreased Ca response amplitude in these regions was observed until four days after CCI. Seven days after CCI, the Ca response amplitude in the contralateral S1 decreased, whereas that in the ipsilateral S1 and contralateral M1 recovered to control levels.
CONCLUSION
These results suggest that neural activity in regions receiving excitatory inputs via corticocortical pathways recovers earlier than in regions receiving thalamocortical inputs. (185/250 words).
PubMed: 38880250
DOI: 10.1016/j.job.2024.06.003 -
Arthritis Research & Therapy Jun 2024Janus kinase (JAK) inhibitors, such as baricitinib, are widely used to treat rheumatoid arthritis (RA). Clinical studies show that baricitinib is more effective at...
Baricitinib ameliorates inflammatory and neuropathic pain in collagen antibody-induced arthritis mice by modulating the IL-6/JAK/STAT3 pathway and CSF-1 expression in dorsal root ganglion neurons.
BACKGROUND
Janus kinase (JAK) inhibitors, such as baricitinib, are widely used to treat rheumatoid arthritis (RA). Clinical studies show that baricitinib is more effective at reducing pain than other similar drugs. Here, we aimed to elucidate the molecular mechanisms underlying the pain relief conferred by baricitinib, using a mouse model of arthritis.
METHODS
We treated collagen antibody-induced arthritis (CAIA) model mice with baricitinib, celecoxib, or vehicle, and evaluated the severity of arthritis, histological findings of the spinal cord, and pain-related behaviours. We also conducted RNA sequencing (RNA-seq) to identify alterations in gene expression in the dorsal root ganglion (DRG) following baricitinib treatment. Finally, we conducted in vitro experiments to investigate the direct effects of baricitinib on neuronal cells.
RESULTS
Both baricitinib and celecoxib significantly decreased CAIA and improved arthritis-dependent grip-strength deficit, while only baricitinib notably suppressed residual tactile allodynia as determined by the von Frey test. CAIA induction of inflammatory cytokines in ankle synovium, including interleukin (IL)-1β and IL-6, was suppressed by treatment with either baricitinib or celecoxib. In contrast, RNA-seq analysis of the DRG revealed that baricitinib, but not celecoxib, restored gene expression alterations induced by CAIA to the control condition. Among many pathways changed by CAIA and baricitinib treatment, the interferon-alpha/gamma, JAK-signal transducer and activator of transcription 3 (STAT3), and nuclear factor kappa B (NF-κB) pathways were considerably decreased in the baricitinib group compared with the celecoxib group. Notably, only baricitinib decreased the expression of colony-stimulating factor 1 (CSF-1), a potent cytokine that causes neuropathic pain through activation of the microglia-astrocyte axis in the spinal cord. Accordingly, baricitinib prevented increases in microglia and astrocytes caused by CAIA. Baricitinib also suppressed JAK/STAT3 pathway activity and Csf1 expression in cultured neuronal cells.
CONCLUSIONS
Our findings demonstrate the effects baricitinib has on the DRG in relation to ameliorating both inflammatory and neuropathic pain.
Topics: Animals; Azetidines; Sulfonamides; Pyrazoles; STAT3 Transcription Factor; Purines; Arthritis, Experimental; Ganglia, Spinal; Neuralgia; Janus Kinases; Signal Transduction; Mice; Interleukin-6; Male; Neurons; Mice, Inbred DBA; Inflammation; Janus Kinase Inhibitors
PubMed: 38879555
DOI: 10.1186/s13075-024-03354-1 -
Experimental Neurology Jun 2024Pain in Parkinson's disease (PD) has been validated as one of the major non-motor dysfunctions affecting the quality of life and subsequent rehabilitation. In the...
Antinociceptive role of the thalamic dopamine D3 receptor in descending modulation of intramuscular formalin-induced muscle nociception in a rat model of Parkinson's disease.
Pain in Parkinson's disease (PD) has been validated as one of the major non-motor dysfunctions affecting the quality of life and subsequent rehabilitation. In the present study, we investigated the role of the dopamine D3 receptor in the thalamic mediodorsal (MD) and ventromedial (VM) nuclei mediated descending control of nociception and intramuscular (i.m.) 2.5% formalin-induced persistent muscle nociception. Paw withdrawal reflexes were measured in naive rats and rats subjected to PD induced by unilateral microinjection of 6 μg 6-OHDA into the rat striatum. Formalin-induced muscle nociception in phase 1, inter-phase, and phase 2 was significantly greater in PD rats compared to naive and vehicle-treated rats (P ˂ 0.001). PD rats exhibited bilaterally mechanical hyperalgesia and heat hypoalgesia in formalin-induced muscle nociception. Microinjection of SK609, a dopamine D3 receptor agonist, at various doses (2.5-7.5 nmol/0.5 μl) into the thalamic VM nucleus dose-dependently prolonged heat-evoked paw withdrawal latencies in both naive and PD rats. Administration of SK609 to either the MD or VM nuclei had no effect on noxious mechanically evoked paw withdrawal reflexes. Pre-treatment of the thalamic MD nucleus with SK609 significantly attenuated formalin-induced nociception, and reversed mechanical hyperalgesia, but not heat hypoalgesia. Pre-treatment of the thalamic VM nucleus with SK609 inhibited formalin-induced nociception in the late phase of phase 2 (30-75 min) and heat hypoalgesia, but not mechanical hyperalgesia (P < 0.05). It is suggested that the dopamine D3 receptors in the thalamus play an antinociceptive role in the descending modulation of nociception. Activation of D3 receptors within the thalamic MD and VM nuclei attenuates descending facilitation and enhances descending inhibition in rats during PD.
PubMed: 38879111
DOI: 10.1016/j.expneurol.2024.114846 -
Neuropharmacology Jun 2024The timing, rate, and quantity of gestational alcohol consumption, collectively referred to here as Maternal Drinking Patterns (MDPs), are of known importance to fetal...
The timing, rate, and quantity of gestational alcohol consumption, collectively referred to here as Maternal Drinking Patterns (MDPs), are of known importance to fetal developmental outcomes. However, few studies have directly evaluated the impact of MDPs on offspring behavior. To do so, we used specialized equipment to record the precise amount and timing of alcohol consumption in pregnant dams, and then characterized MDPs using Principle Component Analysis (PCA). We next tested offspring on behaviors we have previously identified as impacted by prenatal alcohol exposure, and evaluated them where possible in the context of MDPs. Male alcohol exposed mice exhibited longer latencies to fall on the rotarod compared to their controls, which we attribute to a delayed decrease in body weight-gain. This effect was mediated by MDPs within the first 15 min of alcohol access (i.e. alcohol frontloading), where the highest performing male offspring came from dams exhibiting the highest rate of alcohol frontloading. Female alcohol exposed mice displayed reduced locomotor activity in the open field compared to controls, which was mediated by MDPs encompassing the entire drinking session. Surprisingly, total gestational alcohol exposure alone was not associated with any behavioral outcomes. Finally, we observed allodynia in alcohol exposed mice that developed more quickly in males compared to females, and which was not observed in controls. To our knowledge, this report represents the highest resolution assessment of alcohol drinking throughout gestation in mice, and one of few to have identified relationships between specific alcohol MDPs and neurobehavioral outcomes in offspring.
PubMed: 38878859
DOI: 10.1016/j.neuropharm.2024.110044 -
Journal of Neuroimmune Pharmacology :... Jun 2024Chronic neuropathic pain precipitates a complex range of affective and behavioural disturbances that differ markedly between individuals. While the reasons for...
Chronic neuropathic pain precipitates a complex range of affective and behavioural disturbances that differ markedly between individuals. While the reasons for differences in pain-related disability are not well understood, supraspinal neuroimmune interactions are implicated. Minocycline has antidepressant effects in humans and attenuates affective disturbances in rodent models of pain, and acts by reducing neuroinflammation in both the spinal cord and brain. Previous studies, however, tend not to investigate how minocycline modulates individual affective responses to nerve injury, or rely on non-naturalistic behavioural paradigms that fail to capture the complexity of rodent behaviour. We investigated the development and resolution of pain-related affective disturbances in nerve-injured male rats by measuring multiple spontaneous ethological endpoints on a longitudinal naturalistic foraging paradigm, and the effect of chronic oral minocycline administration on these changes. Disrupted foraging behaviours appeared in 22% of nerve-injured rats - termed 'affected' rats - and were present at day 14 but partially resolved by day 21 post-injury. Minocycline completely prevented the emergence of an affected subgroup while only partly attenuating mechanical allodynia, dissociating the relationship between pain and affect. This was associated with a lasting downregulation of ΔFosB expression in ventral hippocampal neurons at day 21 post-injury. Markers of microglia-mediated neuroinflammation were not present by day 21, however proinflammatory microglial polarisation was apparent in the medial prefrontal cortex of affected rats and not in CCI minocycline rats. Individual differences in affective disturbances following nerve injury are therefore temporally related to altered microglial morphology and hippocampal neuronal activation, and are abrogated by minocycline.
Topics: Animals; Minocycline; Male; Rats; Neuroinflammatory Diseases; Rats, Sprague-Dawley; Neuralgia; Hyperalgesia; Individuality; Mood Disorders; Peripheral Nerve Injuries
PubMed: 38878098
DOI: 10.1007/s11481-024-10132-y -
Journal of Bodywork and Movement... Jul 2024Neck pain is a leading cause of disability worldwide. Visceral referred pain is a common form of disease-induced pain, with visceral nociception being referred to...
INTRODUCTION
Neck pain is a leading cause of disability worldwide. Visceral referred pain is a common form of disease-induced pain, with visceral nociception being referred to somatic tissues.
OBJECTIVE
The aim of this case report was to evaluate the immediate and long term effects of a novel osteopathic visceral technique (OVT) on pain and cervical range of motion (CROM) in a patient with nonspecific neck pain (NS-NP).
METHOD
A case of a 47-year-old female suffering with NS-NP for four months. The patient had sought physiotherapy treatment several times, and occasionally used anti-inflammatory medication to relieve symptoms. The patient presented muscle cervical tenderness and hyperalgesia over the spinous processes of C3-C4 spinal segments with limited CROM. A novel osteopathic visceral manipulation (OVM) technique was applied in the epigastric region targeting the pancreas. Immediately after the treatment, the patient reported reduction in pain evaluated with the numerical evaluation scale (NRS), and a clinically significant increase in pressure pain threshold (PPT) in C3 spinous process. Improvement in CROM was also observed. The post-treatment improvements have been maintained at 1-month of follow-up assessment.
CONCLUSION
A single OVT was effective in reducing cervical pain and increasing CROM in a patient with NS-NP caused by a viscerosomatic reflex. The results of this case study provides preliminary evidence that OVM can produce hypoalgesia in somatic tissues with segmentally related innervation. This finding encourages future research to gain a better understanding of the mechanisms of regional inhibitory interdependence involving the viscerosomatic reflexes of OVM.
Topics: Humans; Female; Neck Pain; Manipulation, Osteopathic; Middle Aged; Range of Motion, Articular; Pancreas; Cervical Vertebrae; Pain Measurement
PubMed: 38876625
DOI: 10.1016/j.jbmt.2024.02.028