Significant Motor Impairment Research Articles

Neurorehabilitation of patients with cerebral palsy

Cerebral palsy is one of the common diseases that cause significant motor impairments. This review deals with new methods of motor rehabilitation of children with cerebral palsy in terms of modern physiology, as well as with summarized and analyzed results of experimental studies on the effectiveness of these methods.

PP06.5 – 2643: Clinical profile and radiological characteristics of children with dyskinetic cerebral palsy – An observational study

Objective To study the clinical profile, etiology, radiological characteristics, motor functional ability and severity of dystonia in children with dyskinetic CP. Methods This was an observational study. Sixty-five consecutive children with dyskinetic CP seen between January 2013 and December 2013 were evaluated. For all patients, neuroimaging was done; gross motor function was evaluated using Gross Motor Function Classification System (GMFCS). Video-recordings of each child were made to evaluate resting and task-based dyskinesia using Burke–Fahn–Marsden Scale (BFMS). Results Majority of the dyskinetic children was termborn (80%), weighed >2500 g (72%), age-group 1–2 years (55.4%) and were boys (77%). Dystonia was predominant (91%) as compared to choreo-athetosis (9%). Commonest neonatal problems were neonatal jaundice (79%), sepsis (40%) and birth asphyxia (26%). Main parental concerns were developmental delay (97%), dystonia (60%) and speech problems (26%). 83% were severely disabled and non-ambulatory (level V and IV GMFCS); only onetenth achieved ambulation (Level I and II GMFCS). Mean BFMS score was 45.8+19. Nearly 90% of dystonic children were at level IV and V GMFCS; 67% of choreo-athetotic children were ambulatory. Etiologically, hyperbilirubinemia (66%) and perinatal asphyxia (30%) were predominant. In children with hyperbilirubinemia, mean serum bilirubin was 31+9.4 mg/dL, exchange transfusion done in 60.7%, and 21.5% were G-6-PD deficient. Radiologically, this predominantly involved globus pallidum, substantia nigra and subthalamus; normal scans were seen in 2 children. Perinatal asphyxia led to periventricular-white-matter, putaminal and thalamic changes. The mean dystonia scales were higher in the hyperbilirubinemia group as compared to perinatal asphyxia group. Conclusion Hyperbilirubinemia contributes significantly to severely disabling dyskinetic CP in developing countries. Distinctive radiological patterns of injury help identify the nature of insult. Significant motor impairments and dystonia impair functional abilities of these dyskinetic children.

Forms of therapy of disabled children and role of architecture in this process

The article presents the examples of the different forms of education in the period of building a civil society, and the deliberate creation of equal opportunities and development of the child, foster the construction of curriculum system: "To better developed skills supported the efforts in improving the function of a child with disabilities." Formed integration education and sports centres, primary and secondary s with all facilities where children are educated together in full working order and state disability after diagnosis (with no significant motor impairment), assisted activity of school and educational centres which preparing young people with mild mental retardation - to practical profession, allowing them to actively participate in social life. There has also been a specialist center - Special care for musically gifted children with varying degrees of disability (deaf, visually impaired, cerebral palsy, autism) which appear on stage as an equal alongside the winners of the competitions.

Pain experience and expression in Rett syndrome: Subjective and objective measurement approaches.

Rett syndrome (RTT) is associated with myriad debilitating health issues and significant motor and communicative impairments. Because of the former there is concern about the possibility of recurrent and chronic pain but because of the latter it remains difficult to determine what pain 'looks like' in RTT. This study investigated pain experience and expression using multiple complementary subjective and objective approaches among a clinical RTT sample. Following informed consent, 18 participants (all female) with RTT (mean age= 12.8 years, SD= 6.32) were characterized in terms of pain experience and interference, typical pain expression, and elicited pain behavior during a passive range of motion-like examination procedure. Parents completed the Dalhousie Pain Interview (DPI; pain type, frequency, duration, intensity), the Brief Pain Inventory (BPI; pain interference), and the Non-Communicating Children's Pain Checklist - Revised (NCCPC-R; typical pain expression). A Pain Examination Procedure (PEP) was conducted and scored using the Pain and Discomfort Scale (PADS). The majority of the sample (89%) were reported to experience pain in the previous week which presented as gastrointestinal (n=8), musculoskeletal (n=5), and seizure related pain (n=5) that was intense (scored 0-10; M= 5.67, SD= 3.09) and long in duration (M= 25.22 hours, SD= 53.52). Numerous pain-expressive behaviors were inventoried (e.g., vocal, facial, mood/interaction changes) when parents reported their child's typical pain behaviors and based on independent direct observation during a reliably coded pain exam. This study provides subjective and objective evidence that individuals with RTT experience recurring and chronic pain for which pain expression appears intact.

Adapting to alcohol: Dwarf hamster (Phodopus campbelli) ethanol consumption, sensitivity, and hoard fermentation

Ethanol consumption and sensitivity in many species are influenced by the frequency with which ethanol is encountered in their niches. In Experiment 1, dwarf hamsters (Phodopus campbelli) with ad libitum access to food and water consumed high amounts of unsweetened alcohol solutions. Their consumption of 15%, but not 30%, ethanol was reduced when they were fed a high-fat diet; a high carbohydrate diet did not affect ethanol consumption. In Experiment 2, intraperitoneal injections of ethanol caused significant dose-related motor impairment. Much larger doses administered orally, however, had no effect. In Experiment 3, ryegrass seeds, a common food source for wild dwarf hamsters, supported ethanol fermentation. Results of these experiments suggest that dwarf hamsters may have adapted to consume foods in which ethanol production naturally occurs.

Neuroimaging and neurodevelopmental outcome in extremely preterm infants.

Extremely preterm infants are at risk for neurodevelopmental impairment (NDI). Early cranial ultrasound (CUS) is usual practice, but near-term brain MRI has been reported to better predict outcomes. We prospectively evaluated MRI white matter abnormality (WMA) and cerebellar lesions, and serial CUS adverse findings as predictors of outcomes at 18 to 22 months' corrected age. Early and late CUS, and brain MRI were read by masked central readers, in a large cohort (n = 480) of infants <28 weeks' gestation surviving to near term in the Neonatal Research Network. Outcomes included NDI or death after neuroimaging, and significant gross motor impairment or death, with NDI defined as cognitive composite score <70, significant gross motor impairment, and severe hearing or visual impairment. Multivariable models evaluated the relative predictive value of neuroimaging while controlling for other factors. Of 480 infants, 15 died and 20 were lost. Increasing severity of WMA and significant cerebellar lesions on MRI were associated with adverse outcomes. Cerebellar lesions were rarely identified by CUS. In full multivariable models, both late CUS and MRI, but not early CUS, remained independently associated with NDI or death (MRI cerebellar lesions: odds ratio, 3.0 [95% confidence interval: 1.3-6.8]; late CUS: odds ratio, 9.8 [95% confidence interval: 2.8-35]), and significant gross motor impairment or death. In models that did not include late CUS, MRI moderate-severe WMA was independently associated with adverse outcomes. Both late CUS and near-term MRI abnormalities were associated with outcomes, independent of early CUS and other factors, underscoring the relative prognostic value of near-term neuroimaging.

Interleukin-6 Receptor: A Novel Therapeutic Target for Neuromyelitis Optica

Neuromyelitis optica (NMO) is an inflammatory disorder of the central nervous system causing optic neuritis and transverse myelitis. NMO typically has a worse prognosis than multiple sclerosis due the severity of the acute relapses which lead significant visual and motor impairment. Although the discovery of an NMO-IgG or aquaporin-4 antibody has led to greater understanding about the pathophysiology of the condition, there is currently still no approved treatment for NMO. In this article, will review how IL-6 receptor may be a promising therapeutic target for prevention of NMO relapses.

Transplantation of cerebellar neural stem cells improves motor coordination and neuropathology in Machado-Joseph disease mice.

Machado-Joseph disease is a neurodegenerative disease without effective treatment. Patients with Machado-Joseph disease exhibit significant motor impairments such as gait ataxia, associated with multiple neuropathological changes including mutant ATXN3 inclusions, marked neuronal loss and atrophy of the cerebellum. Thus, an effective treatment of symptomatic patients with Machado-Joseph disease may require cell replacement, which we investigated in this study. For this purpose, we injected cerebellar neural stem cells into the cerebellum of adult Machado-Joseph disease transgenic mice and assessed the effect on the neuropathology, neuroinflammation mediators and neurotrophic factor levels and motor coordination. We found that upon transplantation into the cerebellum of adult Machado-Joseph disease mice, cerebellar neural stem cells differentiate into neurons, astrocytes and oligodendrocytes. Importantly, cerebellar neural stem cell transplantation mediated a significant and robust alleviation of the motor behaviour impairments, which correlated with preservation from Machado-Joseph disease-associated neuropathology, namely reduction of Purkinje cell loss, reduction of cellular layer shrinkage and mutant ATXN3 aggregates. Additionally, a significant reduction of neuroinflammation and an increase of neurotrophic factors levels was observed, indicating that transplantation of cerebellar neural stem cells also triggers important neuroprotective effects. Thus, cerebellar neural stem cells have the potential to be used as a cell replacement and neuroprotective approach for Machado-Joseph disease therapy.

Non-pharmaceutical management of respiratory morbidity in children with severe global developmental delay.

Children with severe global developmental delay (SGDD) have significant intellectual disability and severe motor impairment; they are extremely limited in their functional movement and are dependent upon others for all activities of daily living. SGDD does not directly cause lung dysfunction, but the combination of immobility, weakness, skeletal deformity and parenchymal damage from aspiration can lead to significant prevalence of respiratory illness. Respiratory pathology is a significant cause of morbidity and mortality for children with SGDD; it can result in frequent hospital admissions and impacts upon quality of life. Although many treatment approaches are available, there currently exists no comprehensive review of the literature to inform best practice. A broad range of treatment options exist; to focus the scope of this review and allow in-depth analysis, we have excluded pharmaceutical interventions. To assess the effects of non-pharmaceutical treatment modalities for the management of respiratory morbidity in children with severe global developmental delay. We conducted comprehensive searches of the following databases from inception to November 2013: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, the Allied and Complementary Medicine Database (AMED) and the Cumulative Index to Nursing and Allied Health Literature (CINAHL). We searched the Web of Science and clinical trials registries for grey literature and for planned, ongoing and unpublished trials. We checked the reference lists of all primary included studies for additional relevant references. Randomised controlled trials, controlled trials and cohort studies of children up to 18 years of age with a diagnosis of severe neurological impairment and respiratory morbidity were included. Studies of airways clearance techniques, suction, assisted coughing, non-invasive ventilation, tracheostomy and postural management were eligible for inclusion. We used standard methodological procedures as expected by The Cochrane Collaboration. As the result of heterogeneity, we could not perform meta-analysis. We have therefore presented our results using a narrative approach. Fifteen studies were included in the review. Studies included children with a range of severe neurological impairments in differing settings, for example, home and critical care. Several different treatment modalities were assessed, and a wide range of outcome measures were used. Most studies used a non-randomised design and included small sample groups. Only four randomised controlled trials were identified. Non-randomised design, lack of information about how participants were selected and who completed outcome measures and incomplete reporting led to high or unclear risk of bias in many studies. Results from low-quality studies suggest that use of non-invasive ventilation, mechanically assisted coughing, high-frequency chest wall oscillation (HFCWO), positive expiratory pressure and supportive seating may confer potential benefits. No serious adverse effects were reported for ventilatory support or airway clearance interventions other than one incident in a clinically unstable child following mechanically assisted coughing. Night-time positioning equipment and spinal bracing were shown to have a potentially negative effect for some participants. However, these findings must be considered as tentative and require testing in future randomised trials. This review found no high-quality evidence for any single intervention for the management of respiratory morbidity in children with severe global developmental delay. Our search yielded data on a wide range of interventions of interest. Significant differences in study design and in outcome measures precluded the possibility of meta-analysis. No conclusions on efficacy or safety of interventions for respiratory morbidity in children with severe global developmental delay can be made based upon the findings of this review.A co-ordinated approach to future research is vital to ensure that high-quality evidence becomes available to guide treatment for this vulnerable patient group.

Stroke Survivors Scoring Zero on the NIH Stroke Scale ScoreStill Exhibit Significant Motor Impairment and Functional Limitation

Stroke Survivors Scoring Zero on the NIH Stroke Scale ScoreStill Exhibit Significant Motor Impairment and Functional Limitation

Upper Extremity Exoskeleton for Robot-Aided Rehabilitation

This article discusses development of upper extremity exoskeleton devices for robot-aided rehabilitation. Neurological injuries, including stroke and spinal cord injury, typically result in significant motor impairments. These impairments negatively impact an individual’s movement coordination, in turn affecting their ability to function independently. Exoskeleton type devices are now being developed to isolate the motion of individual joints. These devices tend to have higher complexity and reduced range of motion as compared to endpoint manipulators, but they target more selectively the desired joint(s), and they enable more precise data collection about the motion of the patient's limb. Recent designs have focused on systems that match the full range of motion of the targeted joints, aiming towards actuated systems that have both high torque output, to assist patients with muscle tone, and low intrinsic impedance, to minimally perturb independent arm movements. Satisfying all of these requirements while simultaneously maintaining a high priority on patient safety is still an active area of research.

Erratum to “Stroke Survivors Scoring Zero on the NIH Stroke Scale Score Still Exhibit Significant Motor Impairment and Functional Limitation”

Erratum to “Stroke Survivors Scoring Zero on the NIH Stroke Scale Score Still Exhibit Significant Motor Impairment and Functional Limitation”

Distinct motor impairments of dopamine D1 and D2 receptor knockout mice revealed by three types of motor behavior.

Both D1R and D2R knock out (KO) mice of the major dopamine receptors show significant motor impairments. However, there are some discrepant reports, which may be due to the differences in genetic background and experimental procedures. In addition, only few studies directly compared the motor performance of D1R and D2R KO mice. In this paper, we examined the behavioral difference among N10 congenic D1R and D2R KO, and wild type (WT) mice. First, we examined spontaneous motor activity in the home cage environment for consecutive 5 days. Second, we examined motor performance using the rota-rod task, a standard motor task in rodents. Third, we examined motor ability with the Step-Wheel task in which mice were trained to run in a motor-driven turning wheel adjusting their steps on foothold pegs to drink water. The results showed clear differences among the mice of three genotypes in three different types of behavior. In monitoring spontaneous motor activities, D1R and D2R KO mice showed higher and lower 24 h activities, respectively, than WT mice. In the rota-rod tasks, at a low speed, D1R KO mice showed poor performance but later improved, whereas D2R KO mice showed a good performance at early days without further improvement. When first subjected to a high speed task, the D2R KO mice showed poorer rota-rod performance at a low speed than the D1R KO mice. In the Step-Wheel task, across daily sessions, D2R KO mice increased the duration that mice run sufficiently close to the spout to drink water, and decreased time to touch the floor due to missing the peg steps and number of times the wheel was stopped, which performance was much better than that of D1R KO mice. These incongruent results between the two tasks for D1R and D2R KO mice may be due to the differences in the motivation for the rota-rod and Step-Wheel tasks, aversion- and reward-driven, respectively. The Step-Wheel system may become a useful tool for assessing the motor ability of WT and mutant mice.

Effects of serotonergic medications on locomotor performance in humans with incomplete spinal cord injury.

Incomplete spinal cord injury (iSCI) often results in significant motor impairments that lead to decreased functional mobility. Loss of descending serotonergic (5HT) input to spinal circuits is thought to contribute to motor impairments, with enhanced motor function demonstrated through augmentation of 5HT signaling. However, the presence of spastic motor behaviors in SCI is attributed, in part, to changes in spinal 5HT receptors that augment their activity in the absence of 5HT, although data demonstrating motor effects of 5HT agents that deactivate these receptors are conflicting. The effects of enhancement or depression of 5HT signaling on locomotor function have not been thoroughly evaluated in human iSCI. Therefore, the aim of the current study was to investigate acute effects of 5HT medications on locomotion in 10 subjects with chronic (>1 year) iSCI. Peak overground and treadmill locomotor performance, including measures of gait kinematics, electromyographic (EMG) activity, and oxygen consumption, were assessed before and after single-dose administration of either a selective serotonin reuptake inhibitor (SSRI) or a 5HT antagonist using a double-blinded, randomized, cross-over design. Results indicate that neither medication led to improvements in locomotion, with a significant decrease in peak overground gait speed observed after 5HT antagonists (from 0.8±0.1 to 0.7±0.1 m/s; p=0.01). Additionally, 5-HT medications had differential effects on EMG activity, with 5HT antagonists decreasing extensor activity and SSRIs increasing flexor activity. Our data therefore suggest that acute manipulation of 5HT signaling, despite changes in muscle activity, does not improve locomotor performance after iSCI.

Signaling pathway cross talk in Alzheimer's disease.

Numerous studies suggest energy failure and accumulative intracellular waste play a causal role in the pathogenesis of several neurodegenerative disorders and Alzheimer’s disease (AD) in particular. AD is characterized by extracellular amyloid deposits, intracellular neurofibrillary tangles, cholinergic deficits, synaptic loss, inflammation and extensive oxidative stress. These pathobiological changes are accompanied by significant behavioral, motor, and cognitive impairment leading to accelerated mortality. Currently, the potential role of several metabolic pathways associated with AD, including Wnt signaling, 5' adenosine monophosphate-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), Sirtuin 1 (Sirt1, silent mating-type information regulator 2 homolog 1), and peroxisome proliferator-activated receptor gamma co-activator 1-α (PGC-1α) have widened, with recent discoveries that they are able to modulate several pathological events in AD. These include reduction of amyloid-β aggregation and inflammation, regulation of mitochondrial dynamics, and increased availability of neuronal energy. This review aims to highlight the involvement of these new set of signaling pathways, which we have collectively termed “anti-ageing pathways”, for their potentiality in multi-target therapies against AD where cellular metabolic processes are severely impaired.

Intrastriatal Transplantation of Adenovirus-Generated Induced Pluripotent Stem Cells for Treating Neuropathological and Functional Deficits in a Rodent Model of Huntington's Disease

Induced pluripotent stem cells (iPSCs) show considerable promise for cell replacement therapies for Huntington's disease (HD). Our laboratory has demonstrated that tail-tip fibroblasts, reprogrammed into iPSCs via two adenoviruses, can survive and differentiate into neuronal lineages following transplantation into healthy adult rats. However, the ability of these cells to survive, differentiate, and restore function in a damaged brain is unknown. To this end, adult rats received a regimen of 3-nitropropionic acid (3-NP) to induce behavioral and neuropathological deficits that resemble HD. At 7, 21, and 42 days after the initiation of 3-NP or vehicle, the rats received intrastriatal bilateral transplantation of iPSCs. All rats that received 3-NP and vehicle treatment displayed significant motor impairment, whereas those that received iPSC transplantation after 3-NP treatment had preserved motor function. Histological analysis of the brains of these rats revealed significant decreases in optical densitometric measures in the striatum, lateral ventricle enlargement, as well as an increase in striosome size in all rats receiving 3-NP when compared with sham rats. The 3-NP-treated rats given transplants of iPSCs in the 7- or 21-day groups did not exhibit these deficits. Transplantation of iPSCs at the late-stage (42-day) time point did not protect against the 3-NP-induced neuropathology, despite preserving motor function. Transplanted iPSCs were found to survive and differentiate into region-specific neurons in the striatum of 3-NP rats, at all transplantation time points. Taken together, these results suggest that transplantation of adenovirus-generated iPSCs may provide a potential avenue for therapeutic treatment of HD.

Behavioral and Histopathological Assessment of Adult Ischemic Rat Brains after Intracerebral Transplantation of NSI-566RSC Cell Lines

Stroke is a major cause of death and disability, with very limited treatment option. Cell-based therapies have emerged as potential treatments for stroke. Indeed, studies have shown that transplantation of neural stem cells (NSCs) exerts functional benefits in stroke models. However, graft survival and integration with the host remain pressing concerns with cell-based treatments. The current study set out to investigate those very issues using a human NSC line, NSI-566RSC, in a rat model of ischemic stroke induced by transient occlusion of the middle cerebral artery. Seven days after stroke surgery, those animals that showed significant motor and neurological impairments were randomly assigned to receive NSI-566RSC intracerebral transplants at two sites within the striatum at three different doses: group A (0 cells/µl), group B (5,000 cells/µl), group C (10,000 cells/µl), and group D (20,000 cells/µl). Weekly behavioral tests, starting at seven days and continued up to 8 weeks after transplantation, revealed dose-dependent recovery from both motor and neurological deficits in transplanted stroke animals. Eight weeks after cell transplantation, immunohistochemical investigations via hematoxylin and eosin staining revealed infarct size was similar across all groups. To identify the cell graft, and estimate volume, immunohistochemistry was performed using two human-specific antibodies: one to detect all human nuclei (HuNu), and another to detect human neuron-specific enolase (hNSE). Surviving cell grafts were confirmed in 10/10 animals of group B, 9/10 group C, and 9/10 in group D. hNSE and HuNu staining revealed similar graft volume estimates in transplanted stroke animals. hNSE-immunoreactive fibers were also present within the corpus callosum, coursing in parallel with host tracts, suggesting a propensity to follow established neuroanatomical features. Despite absence of reduction in infarct volume, NSI-566RSC transplantation produced behavioral improvements possibly via robust engraftment and neuronal differentiation, supporting the use of this NSC line for stroke therapy.

Stroke Survivors Scoring Zero on the NIH Stroke Scale Score Still Exhibit Significant Motor Impairment and Functional Limitation.

Objective. To determine the National Institutes of Health Stroke Scale's (NIHSS's) association with upper extremity (UE) impairment and functional outcomes. Design. Secondary, retrospective analysis of randomized controlled trial data. Setting. Not applicable. Participants. 146 subjects with stable, chronic stroke-induced hemiparesis. Intervention. The NIHSS, the UE Fugl-Meyer (FM), and the Arm Motor Ability Test (AMAT) were administered prior to their participation in a multicenter randomized controlled trial. Main Outcome Measures. The NIHSS, FM, and AMAT. Results. The association between the NIHSS and UE impairment was statistically significant (P = −0.204; p = 0.014) but explained less than 4% of the variance among UE FM scores. The association between NIHSS total score and function as measured by the AMAT was not statistically significant (P = −0.141; p = 0.089). Subjects scoring a “zero” on the NIHSS exhibited discernible UE motor deficits and varied scores on the UE FM and AMAT. Conclusion. While being used in stroke trials, the NIHSS may have limited ability to discriminate between treatment responses, even when only a relatively narrow array of impairment levels exists among patients. Given these findings, NIHSS use should be restricted to acute stroke studies and clinical settings with the goal of reporting stroke severity.

RAAV2/7 vector-mediated overexpression of alpha-synuclein in mouse substantia nigra induces protein aggregation and progressive dose-dependent neurodegeneration

BackgroundAlpha-synuclein is a key protein implicated in the pathogenesis of Parkinson's disease (PD). It is the main component of the Lewy bodies, a cardinal neuropathological feature in the disease. In addition, whole locus multiplications and point mutations in the gene coding for alpha-synuclein lead to autosomal dominant monogenic PD. Over the past decade, research on PD has impelled the development of new animal models based on alpha-synuclein. In this context, transgenic mouse lines have failed to reproduce several hallmarks of PD, especially the strong and progressive dopaminergic neurodegeneration over time that occurs in the patients. In contrast, viral vector-based models in rats and non-human primates display prominent, although highly variable, nigral dopaminergic neuron loss. However, the few studies available on viral vector-mediated overexpression of alpha-synuclein in mice report a weak neurodegenerative process and no clear Lewy body-like pathology. To address this issue, we performed a comprehensive comparative study of alpha-synuclein overexpression by means of recombinant adeno-associated viral vectors serotype 2/7 (rAAV2/7) at different doses in adult mouse substantia nigra.ResultsWe noted a significant and dose-dependent alpha-synucleinopathy over time upon nigral viral vector-mediated alpha-synuclein overexpression. We obtained a strong, progressive and dose-dependent loss of dopaminergic neurons in the substantia nigra, reaching a maximum of 82% after 8 weeks. This effect correlated with a reduction in tyrosine hydroxylase immunoreactivity in the striatum. Moreover, behavioural analysis revealed significant motor impairments from 12 weeks after injection on. In addition, we detected the presence of alpha-synuclein-positive aggregates in the remaining surviving neurons. When comparing wild-type to mutant A53T alpha-synuclein at the same vector dose, both induced a similar degree of cell death. These data were supported by a biochemical analysis that showed a net increase in soluble and insoluble alpha-synuclein expression over time to the same extent for both alpha-synuclein variants.ConclusionsIn conclusion, our in vivo data provide evidence that strong and significant alpha-synuclein-induced neuropathology and progressive dopaminergic neurodegeneration can be achieved in mouse brain by means of rAAV2/7.

Novel fentanyl-based dual μ/δ-opioid agonists for the treatment of acute and chronic pain

Approximately one third of the adult U.S. population suffers from some type of on-going, chronic pain annually, and many more will have some type of acute pain associated with trauma or surgery. First-line therapies for moderate to severe pain include prescriptions for common mu opioid receptor agonists such as morphine and its various derivatives. The epidemic use, misuse and diversion of prescription opioids have highlighted just one of the adverse effects of mu opioid analgesics. Alternative approaches include novel opioids that target delta or kappa opioid receptors, or compounds that interact with two or more of the opioid receptors. AimsHere we report the pharmacology of a newly synthesized bifunctional opioid agonist (RV-Jim-C3) derived from combined structures of fentanyl and enkephalin in rodents. RV-Jim-C3 has high affinity binding to both mu and delta opioid receptors. Main methodsMice and rats were used to test RV-Jim-C3 in a tailflick test with and without opioid selective antagonist for antinociception. RV-Jim-C3 was tested for anti-inflammatory and antihypersensitivity effects in a model of formalin-induced flinching and spinal nerve ligation. To rule out motor impairment, rotarod was tested in rats. Key findingsRV-Jim-C3 demonstrates potent-efficacious activity in several in vivo pain models including inflammatory pain, antihyperalgesia and antiallodynic with no significant motor impairment. SignificanceThis is the first report of a fentanyl-based structure with delta and mu opioid receptor activity that exhibits outstanding antinociceptive efficacy in neuropathic pain, reducing the propensity of unwanted side effects driven by current therapies that are unifunctional mu opioid agonists.