Effects of the phosphodiesterase type-5 inhibitor tadalafil on nociception, morphine analgesia and tolerance in rats

Aim: Tadalafil is a potent, selective and reversible inhibitor of phosphodiesterase type 5 (PDE5) enzyme breakdowning cyclic guanosine monophosphate (cGMP). In this study, we aimed to investigate the effects of tadalafil on nociception, morphine analgesia and tolerance. Methods: In this study, 54 Wistar Albino (230-250 g) male rats were used. First of all, four different doses (2, 4, 8, 16 mg/kg) were used to determine the optimum effective dose of tadalafil on nociception. Optimum activity was found at 8 mg/kg and animals were divided into six groups: Saline (S), 8mg/kg tadalafil, 5mg/kg morphine (M), M+ tadalafil, morphine tolerance (MT) and MT+ tadalafil. Saline was given to the control group, tadalafil intraperitoneally and morphine subcutaneously administered at the indicated doses. To develop tolerance to morphine, 10mg/kg morphine was injected daily in the morning and evening for five days and tolerance was evaluated with single dose of morphine on sixth days. The resulting analgesic effect was measured with hot plate and tail flick analgesia tests and recorded at 30th, 60th, 90th and 120th minutes. Results: Tadalafil showed anti-nociceptive effect when given alone at different doses (p<0.05). However, tadalafil significantly decreased the analgesic effect of morphine (p<0.05). In addition, tadalafil significantly increased the tolerance to morphine (p<0.05). Conclusions: The phosphodiesterase type 5 inhibitor tadalafil have anti-nociceptive properties and it decreases analgesic effect of morphine, in addition improves tolerance development. These effects probably may occur via NO/cGMP pathway. &nbsp

Role of dopaminergic system in oxytocin analgesia: The missing part in a puzzle

Purpose: To investigate the analgesic effects of oxytocin (OT) and elucidate the role of dopaminergic system in its mechanisms.Methods: In this study, 72 male (n=6 for each group) 230-250 gr Wistar Albino rats were used. Firstly, dose studies were performed with 100 μg/kg, 200 μg/kg and 400 μg/kg to determine the optimal analgesic effect of oxytocin. Optimal dose was found at 200 μg/kg, and then animals were divided into nine groups: Saline, D1 agonist (SKF 38393; 0.1 mg/kg), D1 antagonist (SCH-23390; 0.1 mg/kg), D1 agonist + oxytocin, D1 antagonist + oxytocin, D2 agonist (Cabergoline; 0,5 mg/kg), D2 antagonist (Sulpride; 10 mg/kg), D2 agonist + oxytocin and D2 antagonist + oxytocin. Serum physiologic saline was given to the saline group and other drugs were administered intraperitoneally at the indicated doses. Tail-flick and hot-plate tests were used to measure analgesic effects. Analgesic tests were measured in 30 min-intervals (at 30th, 60th, 90th, and 120th min) and recorded in seconds. To evaluate maximum antinociceptive effect (% MPE), the tail-flick and hot-plate latencies were converted to the antinociceptive effectivenessResults: The results show that D1 antagonist SCH-23390 (0.1 mg/kg) and D2 agonist cabergoline (0.5 mg/kg) created strong analgesia while the D1 agonist SKF 38393 (0.1 mg/kg) and D2 antagonist sulpiride (10 mg/kg) did not have any analgesic effect. However, only D2 antagonist sulpiride blocked the analgesic effect produced by OTConclusion: OT may be one of the primary agents participating in spinal analgesia, and the dopaminergic system is one of the central mechanisms of action for this important molecule. The dopaminergic system may also be one of the targets for ‘descending’ analgesic system. Keywords: Oxytocin, Tail flick, Hot plate, Dopaminergic, Analgesic, Antagonist, Agonis

Volume CXIV, Number 4, November 7, 1996

Objective: Turner syndrome (TS) is a chromosomal disorder caused by complete or partial X chromosome monosomy that manifests various clinical features depending on the karyotype and on the genetic background of affected girls. This study aimed to systematically investigate the key clinical features of TS in relationship to karyotype in a large pediatric Turkish patient population.Methods: Our retrospective study included 842 karyotype-proven TS patients aged 0-18 years who were evaluated in 35 different centers in Turkey in the years 2013-2014.Results: The most common karyotype was 45,X (50.7%), followed by 45,X/46,XX (10.8%), 46,X,i(Xq) (10.1%) and 45,X/46,X,i(Xq) (9.5%). Mean age at diagnosis was 10.2±4.4 years. The most common presenting complaints were short stature and delayed puberty. Among patients diagnosed before age one year, the ratio of karyotype 45,X was significantly higher than that of other karyotype groups. Cardiac defects (bicuspid aortic valve, coarctation of the aorta and aortic stenosis) were the most common congenital anomalies, occurring in 25% of the TS cases. This was followed by urinary system anomalies (horseshoe kidney, double collector duct system and renal rotation) detected in 16.3%. Hashimoto's thyroiditis was found in 11.1% of patients, gastrointestinal abnormalities in 8.9%, ear nose and throat problems in 22.6%, dermatologic problems in 21.8% and osteoporosis in 15.3%. Learning difficulties and/or psychosocial problems were encountered in 39.1%. Insulin resistance and impaired fasting glucose were detected in 3.4% and 2.2%, respectively. Dyslipidemia prevalence was 11.4%.Conclusion: This comprehensive study systematically evaluated the largest group of karyotype-proven TS girls to date. The karyotype distribution, congenital anomaly and comorbidity profile closely parallel that from other countries and support the need for close medical surveillance of these complex patients throughout their lifespa

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Ghrelin receptor agonist hexarelin attenuates antinociceptive tolerance to morphine in rats

Ghrelin is a peptide hormone released from the gastric endocrine glands and shows analgesic activity apart from its various physiological effects. Nevertheless, the effects of ghrelin receptor (GHS-R) agonists on morphine analgesia and tolerance have not been elucidated yet. The purpose of the study was to evaluate the effects of the ghrelin receptor agonist hexarelin and antagonist [D-Lys3]-GHRP-6 on morphine antinociception and tolerance in rats. A total of 104 Wistar albino male adults rats (weighing approximately 220-240 g) were used in the experiments. To induce morphine tolerance a 3-day cumulative dose regimen was used in rats. Then, randomly selected rats were evaluated for morphine tolerance on day 4. The analgesic effects of hexarelin (0.2 mg/kg), [D-Lys3]-GHRP-6 (10 mg/kg), and morphine (5 mg/kg) were measured at 30-min intervals (0, 30, 60, 90, and 120 min) by tail-flick and hot-plate analgesia tests. The findings suggest that hexarelin in combination with morphine attenuates analgesic tolerance to morphine. On the other hand, ghrelin receptor antagonist [D-Lys3]-GHRP-6 has no significant analgesic activity on the morphine tolerance in analgesia tests. Besides, co-administration of hexarelin and morphine increases the analgesic effect. In conclusion, these data indicate that administration of GHS-R agonist hexarelin with morphine enhances the antinociception and attenuates morphine tolerance.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author