Effects of sex and estrous cycle on intravenous oxycodone self-administration and the reinstatement of oxycodone-seeking behavior in rats.

Introduction: The increasing misuse of both prescription and illicit opioids has culminated in a national healthcare crisis in the United States. Oxycodone is among the most widely prescribed and misused opioid pain relievers and has been associated with a high risk for transition to compulsive opioid use. Here, we sought to examine potential sex differences and estrous cycle-dependent effects on the reinforcing efficacy of oxycodone, as well as on stress-induced or cue-induced oxycodone-seeking behavior, using intravenous (IV) oxycodone self-administration and reinstatement procedures. Methods: In experiment 1, adult male and female Long-Evans rats were trained to self-administer 0.03 mg/kg/inf oxycodone according to a fixed-ratio 1 schedule of reinforcement in daily 2-h sessions, and a dose-response function was subsequently determined (0.003-0.03 mg/kg/inf). In experiment 2, a separate group of adult male and female Long-Evans rats were trained to self-administer 0.03 mg/kg/inf oxycodone for 8 sessions, followed by 0.01 mg/kg/inf oxycodone for 10 sessions. Responding was then extinguished, followed by sequential footshock-induced and cue-induced reinstatement tests. Results: In the dose-response experiment, oxycodone produced a typical inverted U-shape function with 0.01 mg/kg/inf representing the maximally effective dose in both sexes. No sex differences were detected in the reinforcing efficacy of oxycodone. In the second experiment, the reinforcing effects of 0.01-0.03 mg//kg/inf oxycodone were significantly attenuated in females during proestrus/estrus as compared to metestrus/diestrus phases of the estrous cycle. Neither males nor females displayed significant footshock-induced reinstatement of oxycodone seeking, but both sexes exhibited significant cue-induced reinstatement of oxycodone seeking at magnitudes that did not differ either by sex or by estrous cycle phase. Discussion: These results confirm and extend previous work suggesting that sex does not robustly influence the primary reinforcing effects of oxycodone nor the reinstatement of oxycodone-seeking behavior. However, our findings reveal for the first time that the reinforcing efficacy of IV oxycodone varies across the estrous cycle in female rats.

Effects of sex and estrous cycle on intravenous oxycodone self-administration and the reinstatement of oxycodone-seeking behavior in rats.

The increasing misuse of both prescription and illicit opioids has culminated in a national healthcare crisis in the United States. Oxycodone is among the most widely prescribed and misused opioid pain relievers and has been associated with a high risk for transition to compulsive opioid use. Here, we sought to examine potential sex differences and estrous cycle-dependent effects on the reinforcing efficacy of oxycodone, as well as on stress-induced or cue-induced oxycodone-seeking behavior, using intravenous (IV) oxycodone self-administration and reinstatement procedures. In experiment 1, adult male and female Long-Evans rats were trained to self-administer 0.03 mg/kg/inf oxycodone according to a fixed-ratio 1 schedule of reinforcement in daily 2-hr sessions, and a dose-response function was subsequently determined (0.003-0.03 mg/kg/inf). In experiment 2, a separate group of adult male and female Long-Evans rats were trained to self-administer 0.03 mg/kg/inf oxycodone for 8 sessions, followed by 0.01 mg/kg/inf oxycodone for 10 sessions. Responding was then extinguished, followed by sequential footshock-induced and cue-induced reinstatement tests. In the dose-response experiment, oxycodone produced a typical inverted U-shape function with 0.01 mg/kg/inf representing the maximally effective dose in both sexes. No sex differences were detected in the reinforcing efficacy of oxycodone. In the second experiment, the reinforcing effects of 0.01-0.03 mg//kg/inf oxycodone were significantly attenuated in females during proestrus/estrus as compared to metestrus/diestrus phases of the estrous cycle. Neither males nor females displayed significant footshock-induced reinstatement of oxycodone seeking, but both sexes exhibited significant cue-induced reinstatement of oxycodone seeking at magnitudes that did not differ either by sex or by estrous cycle phase. These results confirm and extend previous work suggesting that sex does not robustly influence the primary reinforcing effects of oxycodone nor the reinstatement of oxycodone-seeking behavior. However, our findings reveal for the first time that the reinforcing efficacy of IV oxycodone varies across the estrous cycle in female rats.

Substrate-Dependent Modulation of SIRT2 by a Fluorescent Probe, 1-Aminoanthracene.

Sirtuin isoform 2 (SIRT2) is an enzyme that catalyzes the removal of acyl groups from lysine residues. SIRT2's catalytic domain has a hydrophobic tunnel where its substrate acyl groups bind. Here, we report that the fluorescent probe 1-aminoanthracene (AMA) binds within SIRT2's hydrophobic tunnel in a substrate-dependent manner. AMA's interaction with SIRT2 was characterized by its enhanced fluorescence upon protein binding (>10-fold). AMA interacted weakly with SIRT2 alone in solution (Kd = 37 µM). However, when SIRT2 was equilibrated with a decanoylated peptide substrate, AMA's affinity for SIRT2 was enhanced ∼10-fold (Kd = 4 µM). The peptide's decanoyl chain and AMA co-occupied SIRT2's hydrophobic tunnel when bound to the protein. In contrast, binding of AMA to SIRT2 was competitive with a myristoylated substrate whose longer acyl chain occluded the entire tunnel. AMA competitively inhibited SIRT2 demyristoylase activity with an IC50 of 21 µM, which was significantly more potent than its inhibition of other deacylase activities. Finally, binding and structural analysis suggests that the AMA binding site in SIRT2's hydrophobic tunnel was structurally stabilized when SIRT2 interacted with a decanoylated or 4-oxononanoylated substrate, but AMA's binding site was less stable when SIRT2 was bound to an acetylated substrate. Our use of AMA to explore changes in SIRT2's hydrophobic tunnel that are induced by interactions with specific acylated substrates has implications for developing ligands that modulate SIRT2's substrate specificity.

The association of leg length and offset reconstruction after total hip arthroplasty with clinical outcomes.

BACKGROUND: Restoring native hip anatomy and biomechanics is important to create a well-functioning hip arthroplasty. This study investigated the association of hip offset and leg length after hip arthroplasty with clinical outcomes, including patient reported outcome measures, the Trendelenburg Test and gait analysis. METHODS: In 77 patients undergoing primary hip arthroplasty for osteoarthritis (age mean = 65 SD = 11 years; BMI mean = 27 SD = 5 kg/m2), hip offset and leg length discrepancy were measured on anteroposterior radiographs. The Western Ontario & McMaster Universities Osteoarthritis Index, the Trendelenburg Test and gait were assessed preoperatively, and at 3 and 12 months postoperatively. An inertial measurement unit was used to derive biomechanical parameters, including spatiotemporal gait parameters and tilt angles of the pelvis. Relationships between radiographic and functional outcomes were investigated, and subgroups of patients with >15% decreased and increased femoral offset were analysed separately. FINDINGS: Patient-reported function scores and clinical tests demonstrated a few significant, weak correlations with radiographic outcomes (Spearman's ρ range = 0.26-0.32; p < 0.05). Undercorrection of femoral offset was associated with lower patient-reported function scores and with more step irregularity as well as step asymmetry during gait. Postoperative leg length inequality was associated with increased frontal plane tilt angle of the pelvis during the Trendelenburg Test and increased sagittal plane motion of the pelvis during gait. Femoral offset subgroups demonstrated no significant differences for patient-reported function scores and outcomes of the Trendelenburg Test and gait analysis. INTERPRETATION: Reduced hip offset and leg length discrepancy following hip arthroplasty seem to be marginally associated with worse clinical outcomes.

A systematic review of shoulder injury prevalence, proportion, rate, type, onset, severity, mechanism and risk factors in female artistic gymnasts.

OBJECTIVES: Systematically review shoulder injury prevalence, proportion, rate, type, onset, severity, mechanism, risk factors in female artistic gymnasts. METHODS: PubMed, Web of Science, Scopus, Cochrane Library were searched on 7/01/2017. Original studies reporting data for female artistic gymnasts only, of any age or level were included. Quality assessment was undertaken using Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. RESULTS: Fifteen observational studies were included. Thirteen were poor/fair quality. Shoulder injury prevalence (0%-86.9%) was higher in international (29.2%) versus national (20%) gymnasts. As a proportion of all injuries, shoulder injuries made up 4.2%-7.5%. Rates (0.35-5.7/1000 athlete exposures) were greater during practice (5.0/1000) than competition (2.4/1000). Multidirectional instability (33.8%, 37.7%) and musculotendinous injury (26.6%-90.9%) were the most common injury. In four studies 66.2%-100% of total shoulder injuries were acute onset. Most (59.3%) shoulder injuries were minor, 7.4% required surgery and 80% caused symptoms post-retirement. Asymmetric bars were the most frequent mechanism of shoulder injury. One study reported excessive shoulder stretching, hyperlaxity and instability as significant (p < 0.001) potential risk factors. CONCLUSIONS: Shoulder injuries are a problem among female artistic gymnasts. Interventional studies reporting age and competition level-specific data may guide prevention strategy implementation.