Pain Inhibition Research Articles

Modulation of Neuropathic Pain by Glial Regulation in the Insular Cortex of Rats.

The insular cortex (IC) is known to process pain information. However, analgesic effects of glial inhibition in the IC have not yet been explored. The aim of this study was to investigate pain alleviation effects after neuroglia inhibition in the IC during the early or late phase of pain development. The effects of glial inhibitors in early or late phase inhibition in neuropathic pain were characterized in astrocytes and microglia expressions in the IC of an animal model of neuropathic pain. Changes in withdrawal responses during different stages of inhibition were compared, and morphological changes in glial cells with purinergic receptor expressions were analyzed. Inhibition of glial cells had an analgesic effect that persisted even after drug withdrawal. Both GFAP and CD11b/c expressions were decreased after injection of glial inhibitors. Morphological alterations of astrocytes and microglia were observed with expression changes of purinergic receptors. These findings indicate that inhibition of neuroglia activity in the IC alleviates chronic pain, and that purinergic receptors in glial cells are closely related to chronic pain development.

Activation of the Locus Coeruleus Mediated by Designer Receptor Exclusively Activated by Designer Drug Restores Descending Nociceptive Inhibition after Traumatic Brain Injury in Rats.

Disruption of endogenous pain control mechanisms including descending pain inhibition has been linked to several forms of pain including chronic pain after traumatic brain injury (TBI). The locus coeruleus (LC) is the principal noradrenergic (NA) nucleus participating in descending pain inhibition. We therefore hypothesized that selectively stimulating LC neurons would reduce nociception after TBI. All experiments used a well-characterized rat lateral fluid percussion model of TBI. NA neurons were stimulated by administering clozapine N-oxide (CNO) to rats selectively expressing a designer receptor exclusively activated by designer drug (DREADD) viral construct in their LC's. Mechanical nociceptive thresholds were measured using von Frey fibers. The efficacy of diffuse noxious inhibitory control (DNIC), a critical endogenous pain control mechanism, was assessed using the hindpaw administration of capsaicin. Immunohistochemical analyses demonstrated the selective expression of the DREADD construct in LC neurons after stereotactic injection. During the 1st week after TBI, when rats demonstrated hindlimb (HL) nociceptive sensitization, CNO administration provided transient anti-allodynia in DREADD-expressing rats but not in rats injected with control virus. Seven weeks after TBI we observed a complete loss of DNIC in response to capsaicin. However, CNO administration largely restored DNIC in TBI DREADD-expressing rats but not those injected with control virus. Unexpectedly, the effects of LC activation in the DREADD-expressing rats were blocked by the α-1 adrenergic receptor antagonist prazosin, but not the α-2 adrenergic receptor antagonist atipamezole. These results suggest that directly stimulating the LC after TBI can reduce both early and late manifestations of dysfunctional endogenous pain regulation. Clinical approaches to activating descending pain circuits may reduce suffering in those with pain after TBI.

Spinal 5-HT2A receptor is involved in electroacupuncture inhibition of chronic pain.

Knee osteoarthritis (KOA) is a highly prevalent, chronic joint disorder, and it is a typical disease which can develop chronic pain. Our previous study has proved that endocannabinoid (2-AG)-CB1R-GABA-5-HT pathway is involved in electroacupuncture (EA) mediated inhibition of chronic pain. However, it is still unclear which among the 5-HT receptor subtype is involved in EA evoked 5-HT mediated inhibition of chronic pain in the dorsal spinal cord. 5-HT2A is a G protein-coupled receptor and it is involved in 5-HT descending pain modulation system. We found that EA treatment at frequency of 2 Hz +1 mA significantly increased the expression of 5-HT2A receptor in the dorsal spinal cord and intrathecal injection of 5-HT2A receptor antagonist or agonist reversed or mimicked the analgesic effect of EA in each case respectively. Intrathecal injection of a selective GABAA receptor antagonist Bicuculline also reversed the EA effect on pain hypersensitivity. Additionally, EA treatment reversed the reduced expression of GABAA receptor and KCC2 in the dorsal spinal cord of KOA mice. Furthermore, we demonstrated that intrathecal 5-HT2A receptor antagonist/agonist reversed or mimicked the effect of EA up-regulate of KCC2 expression, respectively. Similarly, intrathecal injection of PLC and PKC inhibitors prevented both anti-allodynic effect and up-regulation of KCC2 expression by EA treatment. Our data suggest that EA treatment up-regulated KCC2 expression through activating 5-HT2A-Gq-PLC-PKC pathway and enhanced the inhibitory function of GABAA receptor, thereby inhibiting chronic pain in a mouse model of KOA.

Long Non-coding RNA and mRNA Expression Change in Spinal Dorsal Horn After Exercise in Neuropathic Pain Rats.

Exercise can help inhibition of neuropathic pain (NP), but the related mechanism remains being explored. In this research, we performed the effect of swimming exercise on the chronic constriction injury (CCI) rats. Compared with CCI group, the mechanical withdrawal threshold of rats in the CCI-Swim group significantly increased on the 21st and 28th day after CCI surgery. Second-generation RNA-sequencing technology was employed to investigate the transcriptomes of spinal dorsal horns in the Sham, CCI, and CCI-Swim groups. On the 28th day post-operation, 306 intersecting long non-coding RNAs (lncRNAs) and 173 intersecting mRNAs were observed between the CCI vs Sham group and CCI-Swim vs CCI groups. Then, the biological functions of lncRNAs and mRNAs in the spinal dorsal horn of CCI rats were then analyzed. Taking the results together, this study could provide a novel perspective for the treatment for NP.

LONGITUDINAL RELATION OF CENTRAL PAIN SENSITIZATION TO DEVELOPMENT OF INEFFICIENT DESCENDING PAIN INHIBITION IN KNEE OSTEOARTHRITIS: THE MULTICENTER OSTEOARTHRITIS STUDY

Purpose: Alterations in nociceptive signaling such as central pain sensitization and inefficient conditioned pain modulation (CPM) are common in people with knee osteoarthritis (OA), contributing to pain severity. Central sensitization reflects facilitated ascending signaling, whereas CPM reflects an endogenous analgesic mechanism of descending pain inhibition in resonse to painful stimuli. It is not known if ascending pain facilitation and descending inhibitory pathways are independent of one another, or whether alterations in ascending pathways may affect functioning of descending pain inhibition.

Unique features of central neuropathic pain in multiple sclerosis: Results of a cluster analysis

BackgroundCentral neuropathic pain (CNP) is an excruciating condition, prevalent in up to a third of patients with multiple sclerosis (MS). Identifying CNP among MS patients is particularly challenging considering the ample comorbid chronic pain conditions and sensory disturbances entailed by the disease. The aim was to identify sensory features unique to CNP beyond those of chronic pain and MS.MethodsParticipants were 112 MS patients: 44 with a diagnosis of CNP, 28 with a diagnosis of chronic musculoskeletal pain (MSP), and 40 pain free. Participants underwent testing of thermal and mechanical thresholds, thermal grill illusion (TGI), pain adaptation (PA), and offset analgesia (OA), and chronic pain was characterized. A two‐step cluster analysis was performed, and the association between the cluster membership and the clinical group membership (CNP, MSP, pain free) was evaluated.ResultsThe CNP and MSP groups were similar in most of the chronic pain variables (e.g., severity, location and quality) and MS‐related variables (e.g., type, severity and medication intake). The three created clusters had unique sensory features: (1) ‘Hyposensitivity’ (increased thermal and touch thresholds) characterized the CNP group; (2) ‘Poor inhibition and hyperalgesia’ (worst PA and OA and decreased TGI threshold) characterized the MSP group; and (3) ‘Efficient inhibition’ (best PA and OA, smallest sensory loss) characterized the pain‐free group.ConclusionsThe unique sensory features of CNP and MSP provide insight into their pathophysiology, and evaluating them may increase the ability to provide individually based interventions. Efficient inhibition may protect MS patients from chronic pain.SignificanceCluster analysis among patients with multiple sclerosis (MS) revealed that while central neuropathic pain is associated with thermal and mechanical hypoesthesia, musculoskeletal pain is involved with reduced pain inhibition and hyperalgesia; sensory profiles that provide insights into the mechanisms of these conditions and may promote an individually based pain management.

Incidence and risk factors for pseudosubluxation of the humeral head following proximal humerus fracture.

BackgroundHumeral head pseudosubluxation (HHPS) in relation to the glenohumeral joint is a common finding following fractures of the proximal humerus. The temporary inferior subluxation of the humeral head may be secondary to a transient axillary nerve neuropraxia, pain inhibition of the deltoid, or hemarthrosis or capsular disruption that alters the physiologically negative pressure in the glenohumeral joint. Despite the frequency of this finding, it is not well described in the literature. This study sought to describe the incidence, risk factors, and rate of resolution of HHPS following proximal humerus fracture.MethodsThe practice of two fellowship-trained shoulder and elbow surgeons was queried for proximal humerus fractures. Patient radiographs were reviewed at the time of injury and all subsequent follow-ups through one year after injury. Data collection included the presence of HHPS, type of fracture based on the Neer classification, operative vs. nonoperative management, and resolution of HHPS. Exclusion criteria included skeletally immature patients, fracture-dislocations, patients treated with reverse shoulder arthroplasty, inadequate follow-up, or those patients with incorrect International Classification of Diseases coding.ResultsThe incidence of HHPS was 20.0% (103 out of 515 patients) overall. Patients who required surgical intervention were more likely to develop pseudosubluxation than those who were treated conservatively (P < .001). There was an increasing incidence of pseudosubluxation based on the Neer classification, with 0-part fractures demonstrating a 2.56% (2/78) rate, whereas 4-part fractures were found to have HHPS in 35.1% (20/57) of cases (P < .001). All patients were found to have resolution of their HHPS at the final follow-up or one year after injury. None of age, sex, obesity, or injury to the dominant arm was associated with the occurrence of HHPS. There was, however, a statistically significant difference in the body mass index of those who developed HHPS (28.4, ± 5.77) vs. those who did not (26.2, ± 5.32, P < .01).ConclusionThis retrospective radiographic study is the largest to date investigating the incidence of HHPS following proximal humerus fracture and first to correlate with Neer classification and operative intervention. We found that HHPS occurs in one-fifth of acute proximal humerus fractures and resolves regardless of intervention. More complex fractures, including those with increasing Neer parts or requiring operative intervention, developed HHPS at higher rates than simpler fracture patterns. This study will help both general orthopedists as well as shoulder surgeons understand the epidemiology of HHPS and provide reassurance to patients that PS is a benign finding with expected spontaneous resolution by one year.

Synthesis of Copper Oxide-Based Nanoformulations of Etoricoxib and Montelukast and Their Evaluation through Analgesic, Anti-Inflammatory, Anti-Pyretic, and Acute Toxicity Activities.

Copper oxide nanoparticles (CuO NPs) were synthesized through the coprecipitation method and used as nanocarriers for etoricoxib (selective COX-2 inhibitor drug) and montelukast (leukotriene product inhibitor drug) in combination therapy. The CuO NPs, free drugs, and nanoformulations were investigated through UV/Vis spectroscopy, FTIR spectroscopy, XRD, SEM, and DLS. SEM imaging showed agglomerated nanorods of CuO NPs of about 87 nm size. The CE1, CE2, and CE6 nanoformulations were investigated through DLS, and their particle sizes were 271, 258, and 254 nm, respectively. The nanoformulations were evaluated through in vitro anti-inflammatory activity, in vivo anti-inflammatory activity, in vivo analgesic activity, in vivo anti-pyretic activity, and in vivo acute toxicity activity. In vivo activities were performed on albino mice. BSA denaturation was highly inhibited by CE1, CE2, and CE6 as compared to other nanoformulations in the in vitro anti-inflammatory activity. The in vivo bioactivities showed that low doses (5 mg/kg) of nanoformulations were more potent than high doses (10 and 20 mg/kg) of free drugs in the inhibition of pain, fever, and inflammation. Lastly, CE2 was more potent than that of other nanoformulations.

Both Gender and Agonistic Experience Affect Perceived Pain during the Cold Pressor Test.

Background. Differences in pain perception in athletes have recently been highlighted in the literature. Objectives. To compare gender ratings of perceived pain in athletes with low and high agonistic experiences (N = 200) using the Cold Pressor Test (CPT). Methods. A three-way repeated measures ANOVA to assess both the effects of the athletes’ gender and lower vs. higher agonistic experiences in the intensity of perceived pain at the beginning of the cold box hand immersion (L0) and after a 90 s interval (L1). Results. There was a statistically significant interaction effect between the level of the agonistic experience and gender in the two moments: p < 0.001; ηp2 = 0.266; F(1,49) = 9.771. Simple main effects analysis showed a significative difference for females at L0: F(1,99) = 93.567, p < 0.025, partial η2 = 0.302) and for males at L1: F(1,99) = 173.420, p < 0.025, partial η2 = 0.666. At the initial moment of CPT, the female athletes showed significantly higher perceived intensity than males, regardless of their experience level. After a 90 s interval, a significantly lower pain perception effect associated with the increased competitive experience of male athletes was observed. Female athletes did not appear to benefit from the experience effect on their pain tolerance. Conclusions. The study confirmed a significant difference in pain perception associated with the athletes’ gender and agonistic experience. Separate explanations related to the pattern of pain inhibition and the acquired reduction in pain sensitivity are reported.

Conditioned Pain Modulation in Children: The Effects of Painful and Nonpainful Conditioning Stimuli

Conditioned pain modulation (CPM), a psychophysical measure in which 1 pain stimulus (conditioning stimulus) is used to inhibit another pain stimulus (test stimulus), is an important indicator of endogenous pain inhibition in adults, but is understudied in children. Preliminary evidence suggests that CPM effects are present in healthy children and are more robust in adolescents. However, developmental differences in younger children are not well documented and few studies control for potential distraction effects of the conditioning stimulus (CS). Participants were 54 healthy children aged 6 to 12 years. After a baseline pressure pain threshold (PPT) test, participants underwent 2 conditioning trials in which PPT was assessed while they placed their left hand in a water bath maintained at either 12 °C (painful CS) or 22 °C (nonpainful sham CS) in counterbalanced order. Results revealed a significant CPM effect. PPT values were significantly higher relative to baseline during the painful CS trial; PPT during the nonpainful CS trial did not differ from baseline. There were no significant age differences in magnitude of CPM effect. The results indicate that children as young as 6 years of age demonstrate CPM, suggesting that descending inhibitory pathways may be better developed in young children than previously thought. PerspectiveThis study was successful in producing inhibitory CPM effects in physically healthy children while controlling for sensory distraction. The findings provide strong evidence that the obtained CPM responses cannot be attributed to sensory distraction or other nonspecific effects. Future studies could utilize CPM paradigms to study various aspects of pediatric endogenous pain inhibition, in order to better predict pain responses and improve interventions.

Attenuation of widespread hypersensitivity to noxious mechanical stimuli by inhibition of GABAergic neurons of the right amygdala in a rat model of chronic back pain

Chronic primary low back pain may be associated with hyperalgesia in uninjured tissues and with decreased pain inhibition. Previous studies have shown that the amygdala is involved in pain regulation and chronic pain, that neuronal activity in the amygdala is altered in models of persistent pain, and that the central nucleus of the right amygdala plays an active role in widespread hypersensitivity to noxious stimuli. Behavioral, electrophysiological, biochemical, and chemogenetic methods were used to examine the role of the central nucleus of the right amygdala in hypersensitivity to noxious stimuli in a rat model of chronic back pain induced by a local injection of Complete Freund Adjuvant (CFA) in paraspinal muscles. CFA produced chronic inflammation limited to the injected area. CFA-treated rats showed increased pain-like (liking) behaviors during the formalin test compared with controls. They also showed widespread mechanical hypersensitivity compared with controls, which persisted for 2months. This widespread hypersensitivity was accompanied by altered activity of different types of right amygdala neurons, as shown by extracellular recordings. Plasmatic levels of IL-1β, IL-6, and TNF-α were not elevated after 1 or 2months, indicating that persistent widespread hypersensitivity is not caused by persistent systemic inflammation. However, chemogenetic inhibition of GABAergic neurons in the right amygdala attenuated widespread mechanical hypersensitivity. These findings indicate that chronic widespread mechanical hypersensitivity in a model of chronic back pain can be attenuated by inhibiting GABAergic neurons of the right amygdala, and that widespread hypersensitivity is not maintained by chronic systemic inflammation. The amygdala is a key structure involved in pain perception and modulation. The present results indicate that the GABAergic neurons of its central nucleus are involved in widespread hypersensitivity to noxious stimuli in a rat model of chronic back pain. The inhibition of amygdala GABAergic neurons may be a potential target for future interventions in patients with chronic back pain.

Somatosensory assessments in patients with inflammatory bowel disease: a cross-sectional study examining pain processing pathways and the role of multiple patient factors.

Pain affects the majority of patients with inflammatory bowel disease (IBD), where pain experiences may be influenced by multiple patient factors and changes within central pain processing pathways, termed central sensitization. The current study aimed to investigate pain processing pathways in patients with IBD through somatosensory testing and associations with multiple patient factors. A cross-sectional study of adults with IBD. Assessments included: somatosensory tests [i.e. pressure pain thresholds (PPT), temporal summation (TS), conditioned pain modulation (CPM)], and patient factors (i.e. demographics, comorbidity, sleep quality, psychological, pain severity and interference, and IBD features). Multiple regression analyses explored associations between somatosensory tests and multiple patient factors. Decreased CPM in participants (N = 51) was associated with worse abdominal pain severity and use of biologic therapies (R2 = 0.30, F(5,44) = 5.18, P = 0.001). Increased TS was associated with biologic use (R2 = 0.11, F(1,49) = 6.13, P = 0.017). Decreased PPT at the low back (R2 = 0.29, F(2,48) = 11.21, P < 0.001) and Tibialis anterior (R2 = 0.41, F(2,48) = 18.26, P < 0.001) were associated with female sex and the absence of a stoma. Study results demonstrated associations between multiple patient factors and somatosensory tests in patients with IBD. The absence of a stoma and female sex was associated with greater sensitivity to pressure in two remote body regions, suggestive of widespread hyperalgesia. Worse abdominal pain severity and biologic use were associated with decreased pain inhibition, and biologic use was also associated with increased pain facilitation. These findings suggest the presence of altered pain processing and mechanisms of central sensitization in patients with IBD.

Reliability of conditioned pain modulation in healthy individuals and chronic pain patients: a systematic review and meta-analysis.

Conditioned pain modulation (CPM) is a psychophysical parameter that is used to reflect the efficacy of endogenous pain inhibition. CPM reliability is important for research and potential clinical applications. The aim of this systematic review and meta-analysis was to evaluate the reliability of CPM tests in healthy individuals and chronic pain patients. We searched three databases for peer-reviewed studies published from inception to October 2020: EMBASE, Web of Science and NCBI. Risk of bias and the quality of the included studies were assessed. A meta-analysis with a random effects model was conducted to estimate intraclass correlation coefficients (ICCs). Meta-analysis was performed on 25 papers that examined healthy participants (k=21) or chronic pain patients (k=4). The highest CPM intra-session reliability was with pressure as test stimulus (TS) and ischemic pressure (IP) or cold pressor test (CPT) as conditioning stimulus (CS) in healthy individuals (ICC 0.64, 95% CI 0.45-0.77), and pressure as TS with CPT as CS in patients (ICC 0.77, 95% CI 0.70-0.82). The highest inter-session ICC was with IP as TS and IP or CPT as CS (ICC 0.51, 95% CI 0.42-0.59) in healthy subjects. The only data available in patients for inter-session reliability were with pressure as TS and CPT as CS (ICC 0.44, 95% CI 0.11-0.69). Quality ranged from very good to excellent using the QACMRR checklist. The majority of the studies (24 out of 25) scored inadequate in Kappa coefficient reporting item of the COSMIN-ROB checklist. Pressure and CPT were the TS and CS most consistently associated with good to excellent intra-session reliability in healthy volunteers and chronic pain patients. The inter-session reliability was fair or less for all modalities, both in healthy volunteers and chronic pain patients.

Heart Rate Variability and Pain: A Systematic Review.

Background and Objective: Heart rate variability (HRV) as an index of the autonomic nervous system appears to be related to reactivity to experimental pain stimuli. HRV could better explain the contributions of sympathetic and parasympathetic activity response to nociceptive stimulation. The aim of this study was to systematically review and synthesize the current evidence on HRV in relation to the experience of pain in experimental tasks. Databases and Data Treatment: Studies indexed in the PubMed, PsycINFO, MEDLINE, WebOfScience, and Scopus databases were reviewed for eligibility. Studies on the autonomic response (i.e., HRV) to experimentally induced pain in healthy adults were included. Different methods of pain induction were considered (e.g., thermal, pressure, and electrical). Data were synthesized considering the association between HRV and both pain induction and subjective measures of pain. Results: Seventy-one studies were included. The results underline significant change in both the sympathetic and parasympathetic autonomic nervous systems during the painful stimulation independent of the pain induction method. The autonomic reaction to pain could be affected by several factors, such as sex, age, body mass index, breathing patterns, the intensity of the stimulation, and the affective state. Moreover, an association between the autonomic nervous system and the subjective experience of pain was found. Higher parasympathetic activity was associated with better self-regulation capacities and, accordingly, a higher pain inhibition capacity. Conclusions: HRV appears to be a helpful marker to evaluate nociceptive response in experimentally induced pain. Future studies are also needed in clinical samples to understand better the interindividual changes of autonomic response due to pain stimuli.

Analgesic Properties of Aqueous Leaf Extract of Alchornea cordifolia (Christmas Bush) on Wistar Rats

Disease conditions leading to pain are major healthcare problem worldwide. Incidences of pain related disorders have been on the increase worldwide. Although, several synthetic agents are available in treatment of these disorders, long-term usage has been reported to potentially lead to undesired effect. Hence Analgesic effects of aqueous leaf extract of Alchornea cordifolia on wistar rats were investigated. Twenty wistar rats of both genders weighing between 110-178 g were utilized. Acetic acid was used for induction of pain. The rats were grouped into five groups of 4 per group in each study. Groups 3, 4 and 5 received 400, 800 mg/kg b.w of aqueous extract and reference drug respectively after induction. Groups 1 and 2 served as normal and negative controls. Rats were sacrificed and blood samples collected for hematological and biochemical analyses. Phytochemical screening of the plant revealed the presence of alkaloid, phenolic compounds, Tannins and Quinine. The result showed significant increase (p≤ 0.05) in paw size, and number of writhing in group 2 and non-significant reduction (p ≥ 0.05) in group 4 were seen when contrasted to group 1 and 2 respectively. Highest pain inhibition (16%) was seen in group 4. Significant (p≤0.05) increase in C-reactive protein and nitric oxide concentrations were observed in groups 3 and 4 when contrasted to group 2 in the study. Non-significant differences in all hematological parameters in all treated groups were observed when compared to group 2. Aqueous leaf extract of Alchornae cordifolia displayed an analgesic effect.

The Relationship Between Experienced Discrimination and Pronociceptive Processes in Native Americans: Results From the Oklahoma Study of Native American Pain Risk

Native Americans (NAs) have higher pain rates than the general U.S. population. It has been found that increased central sensitization and reduced pain inhibition are pronociceptive processes that increase pain risk; yet, little attention has focused on the influence of psychosocial factors. Discrimination is a psychosocial factor associated with increased pain in other minoritized groups; however, it is unclear whether it also promotes pain in NAs. This study analyzed data from 269 healthy, pain-free participants (N = 134 non-Hispanic whites [NHWs], N = 135 NAs) from the Oklahoma Study of Native American Pain Risk. Experienced discrimination was measured using the Everyday Discrimination Scale (EDS). Nociceptive processes were measured via static measures of spinal sensitivity (nociceptive flexion reflex [NFR] threshold, 3-stimulation NFR threshold), temporal summation of pain (TS-Pain) and nociceptive flexion reflex (TS-NFR), and conditioned pain modulation of pain (CPM-Pain) and NFR (CPM-NFR). Results demonstrated that greater discrimination was associated with enhanced TS-NFR and impaired CPM-NFR but not static measures of spinal sensitivity or measures of pain modulation (TS-Pain, CPM-Pain). Although the effects of discrimination on outcomes were similar in both groups (not moderated by ethnicity), NAs experienced higher levels of discrimination and therefore discrimination mediated a relationship between ethnicity and impaired CPM-NFR. This indicates experienced discrimination may promote a pain risk phenotype in NAs that involves spinal sensitization resulting from impaired inhibition of spinal nociception without sensitization of pain experience. PerspectiveThis study found that discrimination was associated with spinal sensitization and impaired descending inhibition of spinal nociception. These findings bolster our understanding of how social stressors experienced disproportionately by minoritized groups can contribute to pain outcomes.

A Fully Implantable Miniaturized Liquid Crystal Polymer (LCP)-Based Spinal Cord Stimulator for Pain Control.

Spinal cord stimulation is a therapy to treat the severe neuropathic pain by suppressing the pain signal via electrical stimulation of the spinal cord. The conventional metal packaged and battery-operated implantable pulse generator (IPG) produces electrical pulses to stimulate the spinal cord. Despite its stable operation after implantation, the implantation site is limited due to its bulky size and heavy weight. Wireless communications including wireless power charging is also restricted, which is mainly attributed to the electromagnetic shielding of the metal package. To overcome these limitations, here, we developed a fully implantable miniaturized spinal cord stimulator based on a biocompatible liquid crystal polymer (LCP). The fabrication of electrode arrays in the LCP substrate and monolithically encapsulating the circuitries using LCP packaging reduces the weight (0.4 g) and the size (the width, length, and thickness are 25.3, 9.3, and 1.9 mm, respectively). An inductive link was utilized to wirelessly transfer the power and the data to implanted circuitries to generate the stimulus pulse. Prior to implantation of the device, operation of the pulse generator was evaluated, and characteristics of stimulation electrode such as an electrochemical impedance spectroscopy (EIS) were measured. The LCP-based spinal cord stimulator was implanted into the spared nerve injury rat model. The degree of pain suppression upon spinal cord stimulation was assessed via the Von Frey test where the mechanical stimulation threshold was evaluated by monitoring the paw withdrawal responses. With no spinal cord stimulation, the mechanical stimulation threshold was observed as 1.47 ± 0.623 g, whereas the stimulation threshold was increased to 12.7 ± 4.00 g after spinal cord stimulation, confirming the efficacy of pain suppression via electrical stimulation of the spinal cord. This LCP-based spinal cord stimulator opens new avenues for the development of a miniaturized but still effective spinal cord stimulator.

Mechanistic analysis for suppression of neuropathic pain in circadian clock gene deficient mice

Mechanistic analysis for suppression of neuropathic pain in circadian clock gene deficient mice

Post-traumatic headache: Pathophysiology and management - A review

Background Post-traumatic headache (PTH) is a common secondary headache due to traumatic brain injury. In the past, significant research has been conducted to understand the pathophysiology and treatment options for PTH. However, PTH still lacks evidence-based treatment, and most of the management depends on the primary phenotype observed in the patient. Objective The main objective of this review is to provide a single reference that covers the current understanding of the pathophysiology and the treatment options available for PTH. Methods A detailed literature search on PubMed was performed, and a narrative review was prepared. Results The pathophysiology of PTH is multifactorial. Acute PTH may be attributed to increased peripheral pain sensitization with impaired pain inhibiting pathways. Chronic or persistent PTH may be due to a chronic inflammatory response and peripheral as well as central sensitization. The mechanism responsible for the transition of acute to persistent PTH is unknown. The migraine-like phenotype is reported to be the most prevalent headache type seen in PTH. New targets for preventive treatment have been identified in recent years, such as neuropeptides like calcitonin-gene-related peptide (CGRP), nitric oxide, and glutamate. The preventive pharmacological and non-pharmacological strategies employed for migraine (e.g. anti-CGRP monoclonal antibodies, onabotulinumtoxinA, physical therapy, cognitive and behavioral treatment, and neurostimulation techniques) have shown in preliminary studies that they are potentially efficacious, but large, randomized, double blind, placebo controlled trials are needed to further establish these as treatment options for PTH. Conclusions The lack of evidence-based treatment for PTH has created a need for future large trials to confirm the safety and efficacy of the currently employed treatments.

Transdermal Enhancement Strategy of Lappaconitine: Alteration of Keratin Configuration by Counter-Ion.

The objective of this study was to develop a lappaconitine (LA) transdermal patch with counter-ion to increase the transdermal permeability of the drug, and a theory of counter-ion altering the conformation of the skin keratin was put forward based on the in vitro skin permeation study and physicochemical properties of ion-pairs. Formulation factors including pressure sensitive adhesives (PSAs), drug-loading, counter-ions and molar ratios of counter-ion were screened by in vitro skin permeation study. The optimized formulation was composed of 7% LA, 1.5 mole cinnamic acid and AAOH(PSAcontaining hydroxyl group synthesized byour laboratory) as an adhesive matrix. The optimized patch was evaluated by the pharmacokinetic and analgesic pharmacodynamic studies. AUC0-t and pain inhibition ratio of the optimized patch were 2450.40 ± 848.52 h ng/mL and 81.18%, which showed good absorption into the skin and excellent analgesic effect. The mechanism of facilitated transdermal drug permeation by counter-ion was investigated by ATR-FTIR, thermal analysis, FTIR, XPS and molecular docking. The results indicated that after the formation of ion-pairs, the excess counter-ions would alter the conformation of the skin keratin, thus increasing the transdermal penetration of LA. In conclusion, the LA patch was successfully optimized, and the effect of counter-ions on the skin was clarified at the molecular level. These findings provided additional references for the application of counter-ion in the transdermal drug delivery system.