CARE4Kids Study: Endophenotypes of Persistent Post-Concussive Symptoms in Adolescents: Study Rationale and Protocol.

Treatment of youth concussion during the acute phase continues to evolve, and this has led to the emergence of guidelines to direct care. While symptoms after concussion typically resolve in 14-28 days, a portion (∼20%) of adolescents endorse persistent post-concussive symptoms (PPCS) beyond normal resolution. This report outlines a study implemented in response to the National Institute of Neurological Diseases and Stroke call for the development and initial clinical validation of objective biological measures to predict risk of PPCS in adolescents. We describe our plans for recruitment of a Development cohort of 11- to 17-year-old youth with concussion, and collection of autonomic, neurocognitive, biofluid, and imaging biomarkers. The most promising of these measures will then be validated in a separate Validation cohort of youth with concussion, and a final, clinically useful algorithm will be developed and disseminated. Upon completion of this study, we will have generated a battery of measures predictive of high risk for PPCS, which will allow for identification and testing of interventions to prevent PPCS in the most high-risk youth.

Cannabis constituents for chronic neuropathic pain; reconciling the clinical and animal evidence.

Chronic neuropathic pain is a debilitating pain syndrome caused by damage to the nervous system that is poorly served by current medications. Given these problems, clinical studies have pursued extracts of the plant Cannabis sativa as alternative treatments for this condition. The vast majority of these studies have examined cannabinoids which contain the psychoactive constituent delta-9-tetrahydrocannabinol (THC). While there have been some positive findings, meta-analyses of this clinical work indicates that this effectiveness is limited and hampered by side-effects. This review focuses on how recent preclinical studies have predicted the clinical limitations of THC-containing cannabis extracts, and importantly, point to how they might be improved. This work highlights the importance of targeting channels and receptors other than cannabinoid CB1 receptors which mediate many of the side-effects of cannabis.

Evidence for the Validation of a Single Item Recovery Question (SIRQ) in Children With Mild and Complicated Mild Traumatic Brain Injury.

BACKGROUND: Recovery from a brain injury occurs in varying degrees. The objective of this study was to investigate the concurrent validity of a parent-reported 10-point scale for degree of recovery, Single Item Recovery Question (SIRQ), in children with mild traumatic brain injury (mTBI) or complicated mTBI (C-mTBI) compared with validated assessments of symptom burden (Post-Concussion Symptom Inventory Parent form-PCSI-P) and quality of life (Pediatric Quality of Life Inventory [PedsQL]). METHODS: A survey was sent to parents of children aged five to 18 years who presented to pediatric level I trauma center with mTBI or C-mTBI. Data included parent-reported postinjury recovery and functioning of children. Pearson correlation coefficients (r) were calculated to measure the associations of the SIRQ with the PCSI-P and the PedsQL. Hierarchical linear regression models were used to examine if covariates would increase the predictive value of the SIRQ to the PCSI-P and the PedsQL total scores. RESULTS: Of 285 responses (175 mTBI and 110 C-mTBI) analyzed, Pearson correlation coefficients for the SIRQ to the PCSI-P (r = -0.65, P < 0.001) and PedsQL total and subscale scores were all significant (P < 0.001) with mostly large-sized effects (r ≥ 0.500), regardless of mTBI classification. Covariates, including mTBI classification, age, gender, and years since injury, resulted in minimum changes in the predictive value of the SIRQ to the PCSI-P and the PedsQL total scores. CONCLUSIONS: The findings demonstrate preliminary evidence for the concurrent validity of the SIRQ in pediatric mTBI and C-mTBI.

Association Between Early Return to School Following Acute Concussion and Symptom Burden at 2 Weeks Postinjury.

Importance: Determining how the timing of return to school is related to later symptom burden is important for early postinjury management recommendations. Objective: To examine the typical time to return to school after a concussion and evaluate whether an earlier return to school is associated with symptom burden 14 days postinjury. Design, Setting, and Participants: Planned secondary analysis of a prospective, multicenter observational cohort study from August 2013 to September 2014. Participants aged 5 to 18 years with an acute (<48 hours) concussion were recruited from 9 Canadian pediatric emergency departments in the Pediatric Emergency Research Canada Network. Exposure: The independent variable was the number of days of school missed. Missing fewer than 3 days after concussion was defined as an early return to school. Main Outcomes and Measures: The primary outcome was symptom burden at 14 days, measured with the Post-Concussion Symptom Inventory (PCSI). Symptom burden was defined as symptoms status at 14 days minus preinjury symptoms. Propensity score analyses applying inverse probability of treatment weighting were performed to estimate the relationship between the timing of return to school and symptom burden. Results: This cohort study examined data for 1630 children (mean age [SD] 11.8 [3.4]; 624 [38%] female). Of these children, 875 (53.7%) were classified as having an early return to school. The mean (SD) number of days missed increased across age groups (5-7 years, 2.61 [5.2]; 8-12 years, 3.26 [4.9]; 13-18 years, 4.71 [6.1]). An early return to school was associated with a lower symptom burden 14 days postinjury in the 8 to 12-year and 13 to 18-year age groups, but not in the 5 to 7-year age group. The association between early return and lower symptom burden was stronger in individuals with a higher symptom burden at the time of injury, except those aged 5 to 7 years. Conclusions and Relevance: In this cohort study of youth aged 5 to 18 years, these results supported the growing belief that prolonged absences from school and other life activities after a concussion may be detrimental to recovery. An early return to school may be associated with a lower symptom burden and, ultimately, faster recovery.

Cannabinoids and Opioids Differentially Target Extrinsic and Intrinsic GABAergic Inputs onto the Periaqueductal Grey Descending Pathway.

The midbrain periaqueductal gray (PAG) plays a central role in pain modulation via descending pathways. Opioids and cannabinoids are thought to activate these descending pathways by relieving intrinsic GABAergic inhibition of PAG neurons which project to the rostroventromedial medulla (RVM), a process known as disinhibition. However, the PAG also receives descending extrinsic GABAergic inputs from the central nucleus of the amygdala (CeA) which are thought to inhibit PAG GABAergic interneurons. It remains unclear how opioids and cannabinoids act at these different synapses to control descending analgesic pathways. We used optogenetics, tract tracing and electrophysiology to identify the circuitry underlying opioid and cannabinoid actions within the PAG of male and female rats. It was observed that both RVM-projection and nonprojection PAG neurons received intrinsic-PAG and extrinsic-CeA synaptic inputs, which were predominantly GABAergic. Opioids acted via presynaptic µ-receptors to suppress both intrinsic and extrinsic GABAergic inputs onto all PAG neurons, although this inhibition was greater in RVM-projection neurons. By contrast, cannabinoids acted via presynaptic CB1 receptors to exclusively suppress the direct descending GABAergic input from the CeA onto RVM-projection PAG neurons. These findings indicate the CeA controls PAG output neurons which project to the RVM via parallel direct and indirect GABAergic pathways. While µ-opioids indiscriminately inhibit GABAergic inputs onto all PAG neurons, cannabinoids selectively inhibit a direct extrinsic GABAergic input from the amygdala onto PAG projection neurons. These differential actions of opioids and cannabinoids provide a flexible system to gate the descending control of analgesia from the PAG.SIGNIFICANCE STATEMENT The disinhibition hypothesis of analgesia states that opioids activate the midbrain periaqueductal gray (PAG) descending pathway by relieving the tonic inhibition of projection neurons from GABAergic interneurons. However, the PAG also receives extrinsic GABAergic inputs and is the locus of action of cannabinoid analgesics. Here, we show the relative sensitivity of GABAergic synapses to opioids and cannabinoids within the PAG depends on both the origin of presynaptic inputs and their postsynaptic targets. While opioids indiscriminately inhibit all GABAergic inputs onto all PAG neurons, cannabinoids selectively inhibit a direct extrinsic GABAergic input from the amygdala onto PAG descending projection neurons. These differential actions of opioids and cannabinoids provide a flexible system to gate PAG descending outputs.

MEG measured delta waves increase in adolescents after concussion.

INTRODUCTION: The purpose of this study is to determine if delta waves, measured by magnetoencephalography (MEG), increase in adolescents due to a sports concussion. METHODS: Twenty-four adolescents (age 14-17) completed pre- and postseason MRI and MEG scanning. MEG whole-brain delta power was calculated for each subject and normalized by the subject's total power. In eight high school football players diagnosed with a concussion during the season (mean age = 15.8), preseason delta power was subtracted from their postseason scan. In eight high school football players without a concussion (mean age = 15.7), preseason delta power was subtracted from postseason delta power and in eight age-matched noncontact controls (mean age = 15.9), baseline delta power was subtracted from a 4-month follow-up scan. ANOVA was used to compare the mean differences between preseason and postseason scans for the three groups of players, with pairwise comparisons based on Student's t-test method. RESULTS: Players with concussions had significantly increased delta wave power at their postseason scans than nonconcussed players (p = .018) and controls (p = .027). CONCLUSION: We demonstrate that a single concussion during the season in adolescent subjects can increase MEG measured delta frequency power at their postseason scan. This adds to the growing body of literature indicating increased delta power following a concussion.

Intrathecal Actions of the Cannabis Constituents Δ(9)-Tetrahydrocannabinol and Cannabidiol in a Mouse Neuropathic Pain Model.

(1) Background: The psychoactive and non-psychoactive constituents of cannabis, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), synergistically reduce allodynia in various animal models of neuropathic pain. Unfortunately, THC-containing drugs also produce substantial side-effects when administered systemically. We examined the effectiveness of targeted spinal delivery of these cannabis constituents, alone and in combination. (2) Methods: The effect of acute intrathecal drug delivery on allodynia and common cannabinoid-like side-effects was examined in a mouse chronic constriction injury (CCI) model of neuropathic pain. (3) Results: intrathecal THC and CBD produced dose-dependent reductions in mechanical and cold allodynia. In a 1:1 combination, they synergistically reduced mechanical and cold allodynia, with a two-fold increase in potency compared to their predicted additive effect. Neither THC, CBD nor combination THC:CBD produced any cannabis-like side-effects at equivalent doses. The anti-allodynic effects of THC were abolished and partly reduced by cannabinoid CB1 and CB2 receptor antagonists AM281 and AM630, respectively. The anti-allodynic effects of CBD were partly reduced by AM630. (4) Conclusions: these findings indicate that intrathecal THC and CBD, individually and in combination, could provide a safe and effective treatment for nerve injury induced neuropathic pain.

Mechanisms of endocannabinoid control of synaptic plasticity.

The endogenous cannabinoid transmitter system regulates synaptic transmission throughout the nervous system. Unlike conventional transmitters, specific stimuli induce synthesis of endocannabinoids (eCBs) in the postsynaptic neuron, and these travel backwards to modulate presynaptic inputs. In doing so, eCBs can induce short-term changes in synaptic strength and longer-term plasticity. While this eCB regulation is near ubiquitous, it displays major regional and synapse specific variations with different synapse specific forms of short-versus long-term plasticity throughout the brain. These differences are due to the plethora of pre- and postsynaptic mechanisms which have been implicated in eCB signalling, the intricacies of which are only just being realised. In this review, we shall describe the current understanding and highlight new advances in this area, with a focus on the retrograde action of eCBs at CB1 receptors (CB1Rs). This article is part of the special Issue on 'Cannabinoids'.

Oral efficacy of Δ(9)-tetrahydrocannabinol and cannabidiol in a mouse neuropathic pain model.

The psychoactive and non-psychoactive constituents of cannabis, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), have synergistic analgesic efficacy in animal models of neuropathic pain when injected systemically. However, the relevance of this preclinical synergy to clinical neuropathic pain studies is unclear because many of the latter use oral administration. We therefore examined the oral effectiveness of these phytocannabinoids and their interactions in a mouse chronic constriction injury (CCI) model of neuropathic pain. THC produced a dose-dependent reduction in mechanical and cold allodynia, but also induced side-effects with similar potency. CBD also reduced allodynia, albeit with lower potency than THC, but did not produce cannabinoid-like side-effects at any dose tested. Combination THC:CBD produced a dose-dependent reduction in allodynia, however, it displayed little to no synergy. Combination THC:CBD produced substantial, synergistic side-effects which increased with the proportion of CBD. These findings demonstrate that oral THC and CBD, alone and in combination, have analgesic efficacy in an animal neuropathic pain model. Unlike prior systemic injection studies, combination THC:CBD lacks analgesic synergy when delivered orally. Furthermore, both THC and combination THC:CBD display a relatively poor therapeutic window when delivered orally. This suggests that CBD provides a safer, albeit lower efficacy, oral treatment for nerve injury induced neuropathic pain than THC-containing preparations. This article is part of the special issue on 'Cannabinoids'.

Impact of Self-Efficacy and Affective Functioning on Pediatric Concussion Symptom Severity.

OBJECTIVE: The purpose of this study was to examine whether self-efficacy predicted pediatric concussion symptom severity and explore whether affective mood states (e.g., depression) influenced this relationship. METHOD: Children (8-17 years) who were diagnosed with a concussion within 30 days of injury participated in the study (n = 105). Following a clinical assessment, participants and caregivers completed questionnaires that assessed overall concussion symptom severity and current depression symptoms. Participants also completed ratings capturing self-efficacy for managing concussion recovery. RESULTS: Linear regression models revealed that greater levels of self-efficacy predicted lower parent- (R2 = 0.10, p = .001) and youth-rated (R2 = 0.23, p < .001) concussion symptom severity. Interestingly, depression symptoms moderated the relationship between self-efficacy and concussion symptom severity. CONCLUSIONS: Findings provide initial support for a relationship between self-efficacy and concussion outcomes and highlight the influence of depressive symptoms. Interventions that optimize youth's self-efficacy have the potential to increase treatment adherence, reduce concussion symptom severity, and improve recovery prognosis.

The anticonvulsant zonisamide positively modulates recombinant and native glycine receptors at clinically relevant concentrations.

GABAA and glycine receptors mediate fast synaptic inhibitory neurotransmission. Despite studies showing that activation of cerebral glycine receptors could be a potential strategy in the treatment of epilepsy, few studies have assessed the effects of existing anticonvulsant therapies on recombinant or native glycine receptors. We, therefore, evaluated the actions of a series of anticonvulsants at recombinant human homo-oligomeric glycine receptor α1, α2 and α3 subtypes expressed in Xenopus oocytes using two-electrode voltage-clamp methods, and then assessed the most effective drug at native glycine receptors from entorhinal cortex neurons using whole-cell voltage-clamp recordings. Ganaxolone, tiagabine and zonisamide positively modulated glycine induced currents at recombinant homomeric glycine receptors. Of these, zonisamide was the most efficacious and exhibited an EC50 value ranging between 450 and 560 µM at α1, α2 and α3 subtypes. These values were not significantly different indicating a non-selective modulation of glycine receptors. Using a therapeutic concentration of zonisamide (100 µM), the potency of glycine was significantly shifted from 106 to 56 µM at α1, 185 to 112 µM at α2, and 245 to 91 µM at α3 receptors. Furthermore, zonisamide (100 µM) potentiated exogenous homomeric and heteromeric glycine mediated currents from layer II pyramidal cells of the lateral or medial entorhinal cortex. As therapeutic concentrations of zonisamide positively modulate recombinant and native glycine receptors, we propose that the anticonvulsant effects of zonisamide may, at least in part, be mediated via this action.

Effect of Cognitive and Physical Rest on Persistent Postconcussive Symptoms following a Pediatric Head Injury.

OBJECTIVE: To evaluate the effect of cognitive and physical rest on persistent postconcussive symptoms in a pediatric population. STUDY DESIGN: A prospective cohort study of 5- to 18-year-olds diagnosed with an acute concussion in a tertiary care pediatric emergency department was conducted from December 2016 to May 2019. Participants (n = 119) were followed over 1 month to track days off from school and sports and the development of persistent postconcussive symptoms (residual concussion symptoms beyond 1 month). Participants were dichotomized into minimal (≤2) and moderate (>2) rest, based on days off from school and sports after a concussion. Univariate and multivariable logistic regression analyses were completed to examine associations with persistent postconcussive symptoms. RESULTS: Of the participants in our study, 24% had persistent postconcussive symptoms. Adolescent age, history of prolonged concussion recovery, and headache at presentation were associated with higher odds of persistent postconcussive symptoms in univariate analyses. In a multivariable logistic regression model, only adolescent age was associated with increased odds of persistent postconcussive symptoms. Compared with the minimal cognitive rest group, moderate cognitive rest did not decrease the odds of persistent postconcussive symptoms (aOR, 1.15; 95% CI, 0.44-2.99). Compared with the minimal physical rest group, moderate physical rest also did not decrease the odds of persistent postconcussive symptoms (aOR, 3.17; 95% CI, 0.35-28.78). CONCLUSIONS: Emerging evidence supports early return to light activity for recovery of acute pediatric concussion. Our study adds to this management approach as we did not find that rest from school and sports resulted in a decreased odds of persistent postconcussive symptoms.

Parent-Child Agreement on Postconcussion Symptoms in the Acute Postinjury Period.

OBJECTIVES: To evaluate parent-child agreement on postconcussion symptom severity within 48 hours of injury and examine the comparative predictive power of a clinical prediction rule when using parent or child symptom reporting. METHODS: Both patients and parents quantified preinjury and current symptoms using the Postconcussion Symptom Inventory (PCSI) in the pediatric emergency department. Two-way mixed, absolute measure intraclass correlation coefficients were calculated to evaluate the agreement between patient and parent reports. A multiple logistic regression was run with 9 items to determine the predictive power of the Predicting and Preventing Postconcussive Problems in Pediatrics clinical prediction rule when using the child-reported PCSI. Delong's receiver operating characteristic curve analysis was used to compare the area under the curve (AUC) for the child-report models versus previously published parent-report models. RESULTS: Overall parent-child agreement for the total PCSI score was fair (intraclass correlation coefficient = 0.66). Parent-child agreement was greater for (1) postinjury (versus preinjury) ratings, (2) physical (versus emotional) symptoms, and (3) older (versus younger) children. Applying the clinical prediction rule by using the child-reported PCSI maintained similar predictive power to parent-reported PCSI (child AUC = 0.70 [95% confidence interval: 0.67-0.72]; parent AUC = 0.71 [95% confidence interval: 0.68-0.74]; P = .23). CONCLUSIONS: Overall parent-child agreement on postconcussion symptoms is fair but varies according to several factors. The findings for physical symptoms and the clinical prediction rule have high agreement; information in these domains are likely to be similar regardless of whether they are provided by either the parent or child. Younger children and emotional symptoms show poorer agreement; interviewing both the child and the parent would provide more comprehensive information in these instances.

Decreased neural expression of the noradrenaline transporter in the papillary dermis after partial sciatic nerve lesion.

After peripheral nerve injury, regeneration or collateral sprouting of noradrenergic nerve fibres in the papillary dermis of the injured limb may contribute to sympathetically-maintained pain. The aim of this study was to determine whether noradrenergic nerve fibre regeneration after partial sciatic nerve ligation (PSL) in Wistar rats was accompanied by parallel shifts in expression of the noradrenaline transporter (NAT). Four or 28 days after PSL surgery, immunohistochemistry was used to examine NAT expression in plantar hind paw skin in relation to pan-neuronal markers (class III beta-tubulin and protein gene product 9.5), peptidergic afferents containing calcitonin gene-related peptide (CGRP), nonpeptidergic afferents labelled by isolectin B4 (IB4), and tyrosine hydroxylase (TH), a marker for cutaneous noradrenergic nerve fibres. Most dermal nerve fibre populations decreased shortly after PSL. However, four weeks after PSL, an increase in staining intensity of CGRP and novel expression of TH were observed in the papillary dermis on the injured side. In contrast, neural expression of NAT was reduced in this region. Loss of NAT might have implications for sympathetically-maintained pain, as failure to rapidly clear noradrenaline could exacerbate aberrant sympathetic-sensory signalling between closely apposed noradrenergic and peptidergic nerve fibres.

Inflammation induces developmentally regulated sumatriptan inhibition of spinal synaptic transmission.

BACKGROUND AND PURPOSE: While triptans are used to treat migraine, there is evidence that they also reduce inflammation-induced pain at the spinal level. The cellular mechanisms underlying this spinal enhancement are unknown. We examined whether inflammation alters sumatriptan modulation of synaptic transmission in the rat spinal dorsal horn. EXPERIMENTAL APPROACH: Three to four days following intraplantar injection of complete Freund's adjuvant (CFA) or saline, whole cell recordings of evoked glutamatergic EPSCs were made from lumbar lamina I-II dorsal horn neurons in rat spinal slices KEY RESULTS: In 2- to 3-week-old animals, sumatriptan reduced the amplitude of evoked EPSCs and this was greater in slices from CFA, compared to saline-injected rats. In CFA-injected animals, sumatriptan increased the paired pulse ratio of evoked EPSCs and reduced the rate of spontaneous miniature EPSCs. The 5-HT1B and 5-HT1D agonists CP9 3129 and PNU109291 both inhibited evoked EPSCs in CFA but not saline-injected rats. By contrast, the 5-HT1A agonist R(+)-8-OH-DPAT inhibited evoked EPSCs in saline but not CFA-injected rats. In CFA-injected rats, the sumatriptan-induced inhibition of evoked EPSCs was reduced by the 5-HT1B and 5-HT1D antagonists NAS181 and BRL-15572. Intriguingly, the difference in sumatriptan inhibition between CFA and saline-injected animals was only observed in animals less than 4 weeks old. CONCLUSION AND IMPLICATIONS: These findings indicate that inflammation induces a developmentally regulated 5-HT1B/1D presynaptic inhibition of excitatory transmission into the rat superficial dorsal horn. Thus, triptans could potentially act as spinal analgesic agents for inflammatory pain in the juvenile setting.

Functional Characteristics and Mechanical Performance of PCU Composites for Knee Meniscus Replacement.

The potential use of fiber-reinforced based polycarbonate-urethanes (PCUs) as candidate meniscal substitutes was investigated in this study. Mechanical test pieces were designed and fabricated using a compression molding technique. Ultra-High Molecular Weight Polyethylene (UHMWPE) fibers were impregnated into PCU matrices, and their mechanical and microstructural properties evaluated. In particular, the tensile moduli of the PCUs were found unsuitable, since they were comparatively lower than that of the meniscus, and may not be able to replicate the inherent role of the meniscus effectively. However, the inclusion of fibers produced a substantial increment in the tensile modulus, to a value within a close range measured for meniscus tissues. Increments of up to 227% were calculated with a PCU fiber reinforcement composite. The embedded fibers in the PCU composites enhanced the fracture mechanisms by preventing the brittle failure and plastic deformation exhibited in fractured PCUs. The behavior of the composites in compression varied with respect to the PCU matrix materials. The mechanical characteristics demonstrated by the developed PCU composites suggest that fiber reinforcements have a considerable potential to duplicate the distinct and multifaceted biomechanical roles of the meniscus.

A new mouse line with reduced GluA2 Q/R site RNA editing exhibits loss of dendritic spines, hippocampal CA1-neuron loss, learning and memory impairments and NMDA receptor-independent seizure vulnerability.

Calcium (Ca2+)-permeable AMPA receptors may, in certain circumstances, contribute to normal synaptic plasticity or to neurodegeneration. AMPA receptors are Ca2+-permeable if they lack the GluA2 subunit or if GluA2 is unedited at a single nucleic acid, known as the Q/R site. In this study, we examined mice engineered with a point mutation in the intronic editing complementary sequence (ECS) of the GluA2 gene, Gria2. Mice heterozygous for the ECS mutation (named GluA2+/ECS(G)) had a ~ 20% reduction in GluA2 RNA editing at the Q/R site. We conducted an initial phenotypic analysis of these mice, finding altered current-voltage relations (confirming expression of Ca2+-permeable AMPA receptors at the synapse). Anatomically, we observed a loss of hippocampal CA1 neurons, altered dendritic morphology and reductions in CA1 pyramidal cell spine density. Behaviourally, GluA2+/ECS(G) mice exhibited reduced motor coordination, and learning and memory impairments. Notably, the mice also exhibited both NMDA receptor-independent long-term potentiation (LTP) and vulnerability to NMDA receptor-independent seizures. These NMDA receptor-independent seizures were rescued by the Ca2+-permeable AMPA receptor antagonist IEM-1460. In summary, unedited GluA2(Q) may have the potential to drive NMDA receptor-independent processes in brain function and disease. Our study provides an initial characterisation of a new mouse model for studying the role of unedited GluA2(Q) in synaptic and dendritic spine plasticity in disorders where unedited GluA2(Q), synapse loss, neurodegeneration, behavioural impairments and/or seizures are observed, such as ischemia, seizures and epilepsy, Huntington's disease, amyotrophic lateral sclerosis, astrocytoma, cocaine seeking behaviour and Alzheimer's disease.

Opioid presynaptic disinhibition of the midbrain periaqueductal grey descending analgesic pathway.

BACKGROUND AND PURPOSE: The midbrain periaqueductal grey (PAG) plays a central role in modulating pain through a descending pathway that projects indirectly to the spinal cord via the rostroventral medial medulla (RVM). While opioids are potent analgesics that target the PAG, their cellular actions on descending projection neurons are unclear. EXPERIMENTAL APPROACH: Patch clamp recordings in voltage- and current-clamp mode were made from acutely prepared PAG slices from animals that received retrograde tracer injections into the RVM. KEY RESULTS: The µ-agonist DAMGO reduced GABAergic evoked inhibitory postsynaptic currents (IPSCs) in retro-labelled, RVM-projecting neurons to a greater extent than in unlabelled neurons. The κ-opioid agonist U69593 reduced evoked IPSCs to a similar extent in both neuronal groups, while the δ-opioid agonist deltorphin-II was without effect. DAMGO and U69593 both produced a reduction in the rate, but not amplitude of spontaneous miniature IPSCs and asynchronous evoked IPSCs in retro-labelled neurons. DAMGO and U69593 also suppressed glutamatergic EPSCs in retro-labelled and unlabelled neurons. The DAMGO inhibition of evoked EPSCs, however, was less than that for evoked IPSCs in retro-labelled, but not unlabelled neurons. In current clamp, DAMGO produced a depolarizing increase in evoked postsynaptic potentials in retro-labelled neurons, but directly inhibited unlabelled neurons. CONCLUSION AND IMPLICATIONS: These findings suggest that µ-opioids activate the descending analgesic pathway from the midbrain PAG by a combination of presynaptic disinhibition of RVM-projecting neurons and postsynaptic inhibition of presumptive interneurons.

Endogenous cannabinoid modulation of restraint stress-induced analgesia in thermal nociception.

It is thought that endogenous cannabinoids have a role in the analgesia induced by specific forms of stress. We examined if the role of endogenous cannabinoids is also dependent upon the mode of nociception, and whether this could be altered by drugs which block their enzymatic degradation. In C57BL/6 mice, restraint stress produced analgesia in the hot-plate and plantar tests, two thermal pain assays that engage distinct supraspinal and spinal nociceptive pathways. Stress-induced analgesia in the hot-plate test was abolished by pre-treatment with the opioid receptor antagonist naltrexone but was unaffected by the cannabinoid receptor antagonist 1-(2,4-Dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-4-morpholinyl-1H-pyrazole-3-carboxamide (AM281). By contrast, stress-induced analgesia in the plantar test was abolished by pre-treatment with naltrexone plus AM281, but not by either antagonist individually. Remarkably, inhibiting the breakdown of endocannabinoids, with the dual fatty acid amide hydrolase and monoacylglycerol lipase inhibitor JZL195, rescued stress-induced analgesia in the hotplate test when endogenous opioid signalling was blocked by naltrexone. Furthermore, JZL195 recruited analgesia induced by sub-threshold restraint stress in both thermal pain assays. These findings indicate the role of endocannabinoids in stress-induced analgesia differs with the type of thermal pain behaviour. However, by inhibiting their breakdown, endocannabinoids can be recruited to substitute for endogenous opioid signalling when their activity is blocked, indicating a degree of redundancy between opioid and cannabinoid systems. Together these data suggest targeting endocannabinoid breakdown could provide an alternative, or adjuvant to mainstream analgesics such as opioids.

Novel imaging approaches to screen for breast cancer: Recent advances and future prospects.

AIM OF THE STUDY: Over the past 50 years, the application of mammography - an X-ray of the breast - to screen healthy women has been a successful strategy to reduce breast cancer mortality. The aim of this study was to review the literature on novel imaging approaches that have the potential to replace mammography. METHODS: An online literature search was carried out using PubMed, Google Scholar, ScienceDirect and Google Patents. The search keywords included "breast cancer", "imaging" and "screening", with 51 journal articles and five United States patents being selected for review. Seventeen relevant online sources were also identified and referenced. RESULTS: In addition to full-field digital mammography (FFDM), a further nine imaging modalities were identified for review. These included: digital breast tomosynthesis (DBT); breast computed tomography (BCT); automated breast ultrasound (ABUS); fusion of FFDM and ABUS; fusion of DBT and ABUS; magnetic resonance imaging (MRI); optical imaging; radio-wave imaging; and tactile sensor imaging. Important parameters were considered: diagnostic success (sensitivity and specificity), especially in dense breasts; time to acquire the images; and capital cost of the equipment. CONCLUSIONS: DBT is rapidly replacing FFDM although it still misses invasive cancers in dense tissue. The fusion of ABUS, either with FFDM or DBT, will lead to sensitivity and specificity approaching 100%. The fusion of opto-acoustic imaging with ultrasound holds considerable promise for the future.