Effects of alterations in cannabinoid signaling, alone and in combination with morphine, on pain-elicited and pain-suppressed behavior in mice

Inhibitors of fatty acid amide hydrolase (FAAH) and anandamide (AEA) uptake, which limit the degradation of endogenous cannabinoids, have received interest as potential therapeutics for pain. There is also evidence that endogenous cannabinoids mediate the antinociceptive effects of opioids. Assays of pain-elicited and pain-suppressed behavior have been used to differentiate the effects of drugs that specifically alter nociception from drugs that alter nociception caused by nonspecific effects such as catalepsy or a general suppression of activity. Using such procedures, this study examines the effects of the direct cannabinoid type 1 (CB1) agonist (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol (CP55940), the FAAH inhibitor cyclohexylcarbamic acid 3'-carbamoylbiphenyl-3-yl ester (URB597), and the AEA uptake inhibitor N-(4-hydroxyphenyl) arachidonylamide (AM404). Additional experiments examined these compounds in combination with morphine. CP55940 produced antinociception in assays of pain-elicited, but not pain-suppressed, behavior and disrupted responding in an assay of schedule-controlled behavior. URB597 and AM404 produced antinociception in assays of pain-elicited and pain-suppressed behavior in which acetic acid was the noxious stimulus, but had no effect on the hotplate and schedule-controlled responding. CP55940 in combination with morphine resulted in effects greater than those of morphine alone in assays of pain-elicited and scheduled-controlled behavior but not pain-suppressed behavior. URB597 in combination with morphine resulted in enhanced morphine effects in assays of pain-elicited and pain-suppressed behavior in which diluted acetic acid was the noxious stimulus, but did not alter morphine's effects on the hotplate or schedule-controlled responding. These studies suggest that, compared with direct CB1 agonists, manipulations of endogenous cannabinoid signaling have enhanced clinical potential; however, their effects depend on the type of noxious stimulus.     

Effect of zafirlukast on methacholine and ultrasonically nebulized distilled water challenge in patients with mild asthma

BACKGROUND: Bronchial asthma is a chronic inflammatory disease characterized by airway inflammation and hyperresponsiveness due to the release of multiple mediators, such as cysteinyl-leukotrienes (cys-LTs). OBJECTIVE: Our study was designed to investigate whether oral pretreatment with zafirlukast (a cys-LTs receptor antagonist) reduces bronchoconstriction against methacholine (MC) and ultrasonically nebulized distilled water (UNDW) challenge in patients with mild asthma. METHODS: Fourteen non-atopic patients (8 males, 20-42 years, forced expiratory volume in 1 s (FEV(1)) 97% SD +/- 0.4) with mild, intermittent bronchial asthma performed a sequential weekly pulmonary function test following challenge with MC or UNDW 2 h after zafirlukast or placebo administration, according to a single-blind method. RESULTS: We found that pretreatment with zafirlukast significantly decreased bronchoconstriction MC (maximum FEV(1) drop -10.75% SD +/- 1.89, p < 0.001) and UNDW induced (maximum FEV(1) drop -12% SD +/- 0.15, p < 0.001), while pretreatment with placebo did not protect patients against FEV(1) drop following MC (maximum FEV(1) drop -33.22% SD +/- 1.42, p < 0.001) and UNDW challenge (maximum FEV(1) drop -30.02% SD +/- 0.4, p < 0.001). CONCLUSIONS: Pretreatment with zafirlukast significantly reduced bronchoconstriction against MC and UNDW challenge in individuals with mild intermittent asthma, indicating that cys-LTs receptor antagonists might be useful as preventive therapy in these patients population.     

Lateral wedges alter mediolateral load distributions at the knee joint in obese individuals

Obesity is the primary risk factor for knee osteoarthritis (OA). Greater external knee adduction moments, surrogate measures for medial compartment loading, are present in Obese individuals and may predispose them to knee OA. Laterally wedged insoles decrease the magnitude of the external adduction moment in Obese individuals but it is unknown how they alter the center of pressure on the tibial plateau. A gait analysis was performed on 14 Obese (avg. 29.3 years; BMI range: 30.3–51.6 kg/m²) and 14 lean women (avg. 26.1 years; BMI range: 20.9–24.6 kg/m²) with and without a full‐length, wedged insole. Computed joint angles, joint moments, and knee extensor strength values were input into a musculoskeletal model to estimate center of pressure of the contact force on the tibial plateau. Statistical significance was assessed using a two‐way ANOVA to compare the main effects of group and insole condition (α = 0.05). The insole resulted in a significant (p < 0.01) lateral shift in the center of pressure location in both the Obese and Control groups (mean: 2.9 ± 0.7 and 1.5 ± 0.7 mm, respectively). The insole also significantly reduced the peak external knee adduction moment 1.88 ± 1.82 N m in the Control group (p < 0.01) and 3.62 ± 3.90 N m in the Obese group (p < 0.01). The results of this study indicate the effects of a prophylactic wedged insole for reducing the magnitude of the load on the knee's medial compartment in Obese women who are at risk for knee OA development. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 665–671, 2013     

A test of the functional asymmetry hypothesis in walking

The causes of bilateral asymmetries during able-bodied gait are unclear. These asymmetries may represent a form of functional asymmetry, which has been defined as a consistent task discrepancy between the two lower limbs. According to this theory, the non-dominant lower limb contributes more to support, while the dominant lower limb contributes more to forward propulsion. Impulses due to vertical and propulsive (anterior) ground reaction forces during gait are directly associated with center of mass support and forward propulsion, respectively, but have not yet been investigated in the context of functional asymmetry. The purpose of this study was to compare bilateral ground reaction force impulses to evaluate functional asymmetry as an explanation for gait asymmetries. We hypothesized that if gait asymmetries are functional in nature: (1) vertical impulse (support) would be greater for the non-dominant limb, (2) propulsive impulse would be greater for the dominant limb, and (3) increasing walking speed would cause disproportionate increases in dominant-limb propulsive impulse, relative to the non-dominant limb propulsive impulse. Asymmetry for vertical and propulsive impulses was quantified during slow, preferred, and fast walking in 20 healthy adults. No significant bilateral differences existed between sample means for vertical or propulsive impulses at the slow or preferred speeds, yet dominant-limb propulsive impulse was 7% greater than non-dominant limb propulsive impulse at the fast speed. In conclusion, impulses were generally symmetrical, offering little support for the functional asymmetry idea, except at the fast speed, where contributions to propulsion were greater for the dominant limb.     

Critical decline in fine motor hand movements in human aging.

BACKGROUND: Slowing of motor movements in human aging is a well-known occurrence, but its biologic basis is poorly understood. Reliable quantitation may refine observations of this phenomenon to better aid research on this entity. METHODS: A panel equipped with timing sensors under computer control was used to measure upper extremity movement times in two groups of healthy individuals: adults younger than 60 years of age (n = 56; range, 18-58 years) and adults older than 60 years of age (n = 38; range, 61-94 years). RESULTS: Fine motor performance was better in the dominant hand (p = 0.0007) regardless of age. Adult and aged groups differed on two basic timing measures, which reflect coarse motor and fine motor performance (p < 0.0001). There were no gender differences on either measure. There was a strong effect of task difficulty with age on coarse motor (p < 0.01) and fine motor (p < 0.0001) measures. The fine motor measure of hand performance in healthy individuals correlated in a nonlinear fashion with age for more difficult tasks (r2 = 0.63) but showed a simple linear relation for less-demanding tasks (r2 = 0.5). CONCLUSION: This technique sensitively detects age-related motor performance decline in humans. There may be a critical period in late midlife when fine motor performance decline either begins or abruptly worsens.     

Testing the Impact of Familiarity with Health Benefits Information on Dietary Supplement Choice in Pregnancy: An Online Choice Experiment

To help meet the increased requirements for critical nutrients during and around pregnancy, supplementation with essential nutrients is recommended. This study aims to determine how the previous awareness of nutrient health benefits and/or the provision of this information influences the importance placed on nutrients (folate, iodine, omega-3 fatty acids, and vitamin D) when choosing between dietary supplement products for pregnancy. Discrete choice experiment data were collected as part of a cross-sectional online survey administered to 857 pregnant women living in Australia. Four segments of women were identified that differ in their preference criteria when choosing among dietary supplement products for pregnancy. When choosing between products, the reinforcement of perceived health benefits (i.e., showing information on health benefits to those already aware of the benefits) was most effective at increasing the importance of folate (in all segments) and iodine (in two segments, 63% of the sample). Neither prior awareness of health benefits alone nor information provided at the point-of-purchase without prior awareness were enough to increase the importance of folate. Our findings suggest a need for simultaneous strategies that (1) provide information on health benefits before purchase and (2) ensure that information on health benefits is available at the point-of-purchase.