Jeremy Walsh

Genetic vs. pharmacological inactivation of COMT influences cannabinoid-induced expression of schizophrenia-related phenotypes

Catechol-O-methyltransferase (COMT) is an important enzyme in the metabolism of dopamine and disturbance in dopamine function is proposed to be central to the pathogenesis of schizophrenia. Clinical epidemiological studies have indicated cannabis use to confer a 2-fold increase in risk for subsequent onset of psychosis, with adolescent-onset use conveying even higher risk. There is evidence that a high activity COMT polymorphism moderates the effects of adolescent exposure to cannabis on risk for adult psychosis. In this paper we compared the effect of chronic adolescent exposure to the cannabinoid WIN 55212 on sensorimotor gating, behaviours related to the negative symptoms of schizophrenia, anxiety- and stress-related behaviours, as well as ex-vivo brain dopamine and serotonin levels, in COMT KO vs. wild-type (WT) mice. Additionally, we examined the effect of pretreatment with the COMT inhibitor tolcapone on acute effects of this cannabinoid on sensorimotor gating in C57BL/6 mice. COMT KO mice were shown to be more vulnerable than WT to the disruptive effects of adolescent cannabinoid treatment on prepulse inhibition (PPI). Acute pharmacological inhibition of COMT in C57BL/6 mice also modified acute cannabinoid effects on startle reactivity, as well as PPI, indicating that chronic and acute loss of COMT can produce dissociable effects on the behavioural effects of cannabinoids. COMT KO mice also demonstrated differential effects of adolescent cannabinoid administration on sociability and anxiety-related behaviour, both confirming and extending earlier reports of COMT×cannabinoid effects on the expression of schizophrenia-related endophenotypes.

Agreement and Correlation Between the Straight Leg Raise and Slump Tests in Subjects With Leg Pain

OBJECTIVE The straight leg raise (SLR) and slump tests have traditionally been used to identify nerve root compression arising from disk herniation. However, they may be more appropriate as tests of lumbosacral neural tissue mechanosensitivity. The aim of this study was to determine agreement and correlation between the SLR and slump tests in a population presenting with back and leg pain. METHODS This was an observational, cross-sectional study design. Forty-five subjects with unilateral leg pain were recruited from an outpatient Back Pain Screening Clinic at a large teaching hospital in Ireland. The SLR and slump tests were performed on each side. In the event of symptom reproduction, the ankle was dorsiflexed. Reproduction of presenting symptoms, which were intensified by ankle dorsiflexion, was interpreted as a positive test. An inclinometer was used to measure range of motion (ROM). RESULTS There was substantial agreement between SLR and slump test interpretation (kappa = 0.69) with good correlation in ROM between the 2 tests (r = 0.64) on the symptomatic side. In subjects who had positive results, ROM for both tests was significantly reduced compared to ROM on the contralateral side and ROM in subjects who had negative results. CONCLUSIONS When the SLR and slump tests are interpreted as positive in the event of reproduction of presenting leg pain that are intensified by ankle dorsiflexion, these tests show substantial agreement and good correlation in the leg pain population. When interpreted in this way, these tests may be appropriate tests of neural tissue mechanosensitivity, but further criteria must be met before a definitive conclusion in relation to neural tissue mechanosensitivity may be drawn.

Reliability, validity and diagnostic accuracy of palpation of the sciatic, tibial and common peroneal nerves in the examination of low back related leg pain

This study investigated the reliability, validity and diagnostic accuracy of manual palpation of the sciatic, tibial and common peroneal nerves in the examination of 45 subjects with low-back related leg pain. The nerves were palpated manually and with an algometer, to determine pressure pain thresholds (PPTs). A second examiner performed the straight leg raise (SLR) and slump tests to determine nerve trunk mechanosensitivity. The procedure was repeated by another examiner to determine inter-rater reliability (n = 20). Kappa scores for agreement between raters for manual palpation were 0.80, 0.70 and 0.79 for the sciatic, tibial and common peroneal nerves respectively, demonstrating excellent reliability. PPTs were significantly lower on the symptomatic side, for each of the three nerves, in subjects who were positive on manual palpation. In subjects who were negative on manual palpation, PPTs were not significantly different between sides, demonstrating criterion-based validity, using PPT as the criterion. Highest scores of diagnostic accuracy were obtained when two or more of the three nerves were positive on palpation (sensitivity = 0.83; specificity = 0.73).

Disruption of thermal nociceptive behaviour in mice mutant for the schizophrenia-associated genes NRG1, COMT and DISC1

Abnormalities in pain perception, especially altered warmth and heat pain sensitivity, have been reported in schizophrenia. Therefore, genes associated with schizophrenia, including neuregulin-1 (NRG1), catechol-O-methyltranferase (COMT) and disrupted-in-schizophrenia-1 (DISC1), may play a role in modulating the physiological and psychological effects of pain stimuli in such patients. Thermal pain sensitivity was assessed in NRG1, COMT and DISC1 mutant mice, and the anti-nociceptive effects of acute Delta(9)-tetrahydrocannabinol (THC) were compared in NRG1 and COMT mutants. At baseline, deletion of NRG1 and DISC1 each reduced thermal pain sensitivity, while deletion of COMT increased pain sensitivity. Neither NRG1 nor COMT deletion altered the anti-nociceptive effects of acute systemic THC (8.0mg/kg). These results indicate a differential contribution of NRG1 and DISC1 vis-à-vis COMT to the processing of thermal nociceptive stimuli and extend their phenotypic relationship to psychotic illness.

Effects of the Mulligan Traction Straight Leg Raise Technique on Range of Movement

Abstract The Mulligan traction straight leg raise (SLR) technique is used therapeutically to increase range of SLR when it is limited due to low-back dysfunction or hamstring tightness. The effects of this technique were investigated in 26 normal subjects (mean age 26 years; 13 male). As the movement of SLR comprises hip flexion and posterior pelvic rotation, ranges of SLR and posterior pelvic rotation were measured pre- and post-intervention using two bubble inclinometers. Prior to data collection, SLR was performed four times to minimize increased movement due to repetitive stretch. Following the intervention, the mean range of SLR significantly increased by 13.3° or 27%, from 49.9° to 63.2°. Mean range pelvic rotation also significantly increased but by only 2.7°. Hip flexion was the major reason for increased range of SLR following the intervention, indicating an increase in hamstring muscle stretch tolerance. The possible mechanisms for improvement in range are discussed.

Agreement and correlation between the self-report leeds assessment of neuropathic symptoms and signs and Douleur Neuropathique 4 Questions neuropathic pain screening tools in subjects with low back-related leg pain.

OBJECTIVE The self-report Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS) and Douleur Neuropathique 4 Questions (DN4) neuropathic pain screening tools have been shown to be reliable, valid, and able to differentiate neuropathic pain from inflammatory or mixed pain syndromes. However, no studies have compared these tools to determine whether their outcomes are similar. This study evaluated agreement and correlation between the S-LANSS and DN4 in the identification of neuropathic pain in subjects with low back-related leg pain. METHODS This observational study compared S-LANSS and DN4 scores in 45 patients with low back-related leg pain. The S-LANSS and DN4 cutoff scores of 12 and 4, respectively, were used to classify subjects as positive or negative for the presence of neuropathic pain for each screening tool. The κ statistic was used to determine whether there was agreement in classification of neuropathic pain between the 2 screening tools. Pearson correlation coefficient was used to determine correlation between scores of the 2 screening tools. RESULTS Neuropathic pain was identified in 15 subjects (33%) using the S-LANSS and in 19 subjects (42%) using the DN4. Agreement on neuropathic pain classification was fair, with a κ value of 0.34. There was moderate to good correlation (r = 0.62; P < .001) between scores obtained from the 2 tools. CONCLUSIONS The finding of fair agreement suggests that despite the moderate to good correlation between scores, the cutoff points for the classification of neuropathic pain of the 2 tools may not be congruent.

Classification of low back-related leg pain: do subgroups differ in disability and psychosocial factors?

Abstract It has been proposed that patients with low back-related leg pain can be classified according to pain mechanisms into four distinct subgroups: Central Sensitization (CS), Denervation (D), Peripheral Nerve Sensitization (PNS), and Musculoskeletal (M). The purpose of this study was to determine whether there were any differences in terms of disability and psychosocial factors between these four subgroups. Forty-five subjects with low back-related leg pain completed the Oswestry Disability Index, the Hospital Anxiety and Depression Scale, and the Fear Avoidance Beliefs Questionnaire. Subsequently, an examiner blinded to the questionnaire results classified the subjects into one of the four subgroups, according to the findings of the self-administered Leeds Assessment of Neuropathic Signs and Symptoms questionnaire and a physical examination. It was found that the PNS subgroup had significantly greater disability compared to all other subgroups and significantly greater fear avoidance beliefs about physical activity compared to the CS and D subgroups. This highlights the importance of sub-classification but also the need to take into account disability and psychosocial factors in the management of low back-related leg pain.

Disruption of exploratory and habituation behavior in mice with mutation of DISC1: an ethologically based analysis

Disrupted‐in‐schizophrenia‐1 (DISC1) is a gene that has been functionally linked with neurodevelopmental processes and structural plasticity in the brain. Clinical genetic investigations have implicated DISC1 as a genetic risk factor for schizophrenia and related psychoses. Studies using mutant mouse models of DISC1 gene function have demonstrated schizophrenia‐related anatomical and behavioral endophenotypes. In the present study, ethologically based assessment of exploratory and habituation behavior in the open field was conducted in DISC1 (L100P), wild‐type (WT), heterozygous (HET), and homozygous (HOM) mutant mice of both sexes. Ethological assessment was conducted in an open‐field environment to explore specific topographies of murine exploratory behavior across the extended course of interaction from initial exploration through subsequent habituation (the ethogram). During initial exploration, HET and HOM DISC1 mutants evidenced increased levels of locomotion and rearing to wall compared with WT. A HOM‐specific increase in total rearing and a HET‐specific increase in sifting behavior and reduction in rearing seated were also observed. Over subsequent habituation, locomotion, sniffing, total rearing, rearing to wall, rearing free, and rearing seated were increased in HET and HOM mutants vs. WT. Overall, grooming was increased in HOM relative to other genotypes. HET mice displayed a selective decrease in habituation of sifting behavior. These data demonstrate impairment in both initial exploratory and habituation of exploration in a novel environment in mice with mutation of DISC1. This is discussed in the context of the functional role of the gene vis à vis a schizophrenia phenotype as well as the value of ethologically based approaches to behavioral phenotyping.

Comparative evaluation of the degree of pegylation of poly(lactic-co-glycolic acid) nanoparticles in enhancing central nervous system delivery of loperamide.

In this study, we examined the relative cellular uptake of nanoparticles (NPs) formulated using poly(lactic‐co‐glycolic acid) (PLGA) polymers with increasing degree of pegylation (PLGA‐PEG) and their potential to deliver loperamide to the brain of a mouse.