Opioid and endocannabinoid system in orofacial pain.

Orofacial pain disorders are frequent in the general population and their pharmacological treatment is difficult and controversial. Therefore, the search for novel, safe and efficient analgesics is an important but still elusive goal for contemporary medicine. In the recent years, the antinociceptive potential of endocannabinoids and opioids has been emphasized. However, concerns for the safety of their use limit their clinical applications. the possibility of modulating the activity of endocannabinoids by regulation of their synthesis and/or degradation offers an innovative approach to the treatment of pain. A rat model of trigeminal pain, utilizing tongue jerks evoked by electrical tooth pulp stimulation during perfusion of the cerebral ventricles with various neurotransmitter solutions can be used in the pharmacological studies of nociception in the orofacial area. The aim of this review is to present the effects of pharmacological activity of opioids and endocannabinoids affecting the transmission of the sensory information from the orofacial area on the example of trigemino-hypoglossal reflex in rats.

New Horizons in the Etiopathogenesis and Non-Invasive Diagnosis of Endometriosis.

Endometriosis is one of the most common gynecological inflammatory diseases, occurring in adolescents and women in the reproductive age group and leading to infertility. The precise etiopathogenesis of endometriosis is unknown, but several theories concerning the phenomena involved in its development have been proposed. Beside classic retrograde menstruation, these include lymphatic and vascular metastases, iatrogenic direct implantation, coelomic metaplasia, embryonic remnants and mesenchymal cell differentiation or induction; the persistence of a form of embryonic endometriosis may also be involved, as well as the theory of the possible role of endometrial stem/progenitor cells. This paper deals with other risk factors which may be potentially involved in the etiopathogenesis of endometriosis, including the immune, inflammatory, endocrine, genetic, anatomical and environmental factors. At present, endometriosis can only be diagnosed with surgery, where laparoscopy is considered a gold standard. Therefore, there is an urgent need for a test allowing to detect non-invasive molecular biomarkers to identify the symptoms of endometriosis early on in disease development. A thorough understanding of the etiopathogenesis of endometriosis is essential toward the development of novel diagnostic assays and effective treatments of the disease.

A new face of endocannabinoids in pharmacotherapy. Part I: protective role of endocannabinoids in hypertension and myocardial infarction.

Cannabinoids are compounds which were first isolated from the Cannabis sativa plant. For thousands of years they have been used for treatment of numerous diseases. Currently, synthetic cannabinoids and endocannabinoids are also known. Cannabinoid receptors, endocannabinoids and the enzymes that catalyze their synthesis and degradation constitute the endocannabinoid system which plays an important role in functioning of the cardiovascular system. The results obtained to date suggest the involvement of endocannabinoids in the pathology of many cardiovascular diseases, including myocardial infarction, hypertension and hypotension associated with hemorrhagic, endotoxic, and cardiogenic shock. Cardioprotective effect and dilation of coronary vessels induced by endocannabinoids deserve special attention. It cannot be excluded now that in the future our better understanding of cannabinoid system will allow to develop new strategies for treatment of cardiovascular diseases.

A new face of endocannabinoids in pharmacotherapy. Part II: role of endocannabinoids in inflammation-derived cardiovaascular diseases.

Endocannabinoids play an important role in cardiovascular diseases caused by inflammatory disorders. Endocannabinoids are endogenous bioactive lipids that activate cannabinoid receptors and together with enzymes responsible for their synthesis and degradation constitute endocannabinoid system. The results obtained to date suggest the involvement of endocannabinoids in the pathology of many cardiovascular diseases associated with inflammation, such as atherosclerosis, restenosis, chemotherapy-induced myocardial injury, diabetic and hepatic cirrhosis cardiomyopathy. Our better understanding of cannabinoid system may result in the development of new strategies for the treatment of such disorders.

Body structure and composition of canoeists and kayakers: analysis of junior and teenage polish national canoeing team.

The somatic build, biological age, general state of health, mental predisposition and physical fitness are the criteria for selection of individuals in competitive sport. The present study aims to analys the differences in body structure and composition of canoeists and kayakers and derive conclusions regarding the criteria for selection of individuals incompetitive sport. The research was conducted on a group of 32 men aged between 17 and 22: 16 kayakers and 16 Canadian canoeists of the junior and teenage Polish national canoeing team. Body composition was examined by means of bioelectrical segmental impedance. Body build type was determined using the anthropometric Heath-Carter method. Statistical analysis was performed using the Welch t-test. The examination of morphological features reveals significant differences in the studied parameters between the canoeists and kayakers. There are also significant differences between competitors of the Sydney 2000 Olympic Games and the studied group. We found that competitive kayakers should be taller than canoeists. The lower part of the body in kayakers is more developed than in canoeists and canoeists are more dehydrated than kayakers.

[The effect of intragastric balloon on serum lipids level in patients with morbid obesity]. / Wplyw leczenia balonem wewnatrz-zoladkowym na stezienie lipidów w surowicy u pacjentów z otyloscia olbrzymia.

Obesity is recently considered as the twentieth first century epidemy. An excessive accumulation of adipocytes that constitute metabolically active tissue, plays an important role in lipid and carbohydrate metabolism. In the morbidly obese population dyslipidemia is common. AIM OF OUR STUDY: To determine the content of total cholesterol (TC), HDL-cholesterol (HDL), LDL-cholesterol (LDL) and triacylglicerol (TG) in obese subjects treated with the Bioenterics Intragastric Balloon (BIB). MATERIAL AND METHODS: BIB was placement for 6 months in 21 obese patients, mean age 40 (21-60), with BMI 473 +/- 5.7 kg/m2. The control group consisted of 15 morbidly obese patients treated conservatively. Plasma lipid concentration were assessed by the enzymatic methods. RESULTS: No major complications have been noted in patients with BIB. However, nearly all patients complained of discomfort, nausea and vomiting for the first few days. Over a 6-month-period, a reduction in body mass in the BIB group was 17.1 +/- 8.0 kg as compared to 3.2 +/- 6.4 kg in the control group (p = 0.00003). The biggest reduction in body mass was observed during first month. After one month, total cholesterol (TC) decreased by 17.6% (p < 0.001), triacylglycerol (TG) decreased by 25.5% (p = 0.01), low-density lipoprotein cholesterol (LDL) decreased by 27.5% (p < 0.001). In the control group, the corresponding levels of TC, TG and LDL remained unchanged. The level of HDL increased in both group. CONCLUSIONS: In patients with morbid obesity treated with BIB, weight loss is accompanied by a decrease in concentration TC, LDL and TG and increase in plasma HDL. The reduction of lipid concentration in blood serum may cut down cholesterol-lowering therapy and diminish the risk for development of coronary heart disease.

The effect of intragastric balloon on plasma ghrelin, leptin, and adiponectin levels in patients with morbid obesity.

CONTEXT: Ghrelin and leptin are hormones regulating appetite and metabolic processes. Adiponectin plays an important role in the modulation of glucose and lipid metabolism. OBJECTIVE: The objective of the study was to evaluate the levels of plasma ghrelin, leptin, and adiponectin in obese subjects treated with bioenterics intragastric balloon (BIB), low-calorie diet (1500 kcal), and physical exercise. DESIGN: BIB was placed for 6 months in 21 subjects with body mass index 47.3 +/- 5.7. The control group consisted of 15 morbidly obese subjects treated with a low-calorie diet and physical effort. Plasma hormone levels were determined by RIA. RESULTS: In the BIB group, the insertion of the balloon caused a considerable reduction in body mass over a 6-month period (17.1 +/- 8.0 kg) as compared with the control group (3.2 +/- 6.4 kg). After 1 month, the levels of ghrelin increased from 621.9 +/- 182.4 to 903.9 +/- 237 pg/ml and thereafter gradually decreased, reaching the starting level 3 months after the removal of the balloon. In the same group, the levels of leptin decreased from 61.3 +/- 36.7 to 39.9 +/- 17.5 ng/ml. In the control group, the corresponding levels of ghrelin and leptin remained relatively stable. During the observation period, in the BIB group, the levels of adiponectin remained unchanged as opposed to a transient increase noted in the control group. CONCLUSIONS: In patients with morbid obesity, weight loss induced by BIB is associated with a decrease in plasma leptin and a transient elevation of plasma ghrelin. It is likely that the changes in hormones regulating the energy balance caused by BIB can prevent an increase in adiponectin level.

Interactions of galanin with endomorphin-2, vasopressin and oxytocin in nociceptive modulation of the trigemino-hypoglossal reflex in rats.

Galanin (GAL) is suggested to be a neuropeptide involved in pain transmission. In this study we tried to determine, whether the increase of GAL concentration in brain cells affects impulse transmission between the motor centers localized in the vicinity of the third and fourth cerebral ventricles. The experiments were carried out on rats under chloralose anesthesia. The study objectives were realized using the method allowing to record the amplitude of evoked tongue jerks (ETJ) in response to noxious tooth pulp stimulation during the perfusion of the cerebral ventricles with solutions containing tested compounds. Perfusion of the cerebral ventricles with GAL concentration-dependently inhibited the ETJ amplitude. The antinociceptive effect of GAL was blocked by a galanin receptor antagonist, galantide (GLT) and by opioid antagonists: non-selective naloxone (Nal) and micro-selective beta-funaltrexamine (beta-FNA). In contrast, a delta-opioid receptor antagonist, naltrindole (NTI) or the kappa-opioid receptor antagonist, nor-binaltrophimine (nor-BNI) did not inhibit the effect of GAL. The antinociceptive effect of GAL was more pronounced when GAL was perfused in combination with other neuropeptides/neurohormones, such as endomorphin-2 (EM-2), vasopressin (AVP) and oxytocin (OT). The present results demonstrate that in the orofacial area analgesic activity is modulated by GAL, OT and AVP and that EM-2-induced antinociception involves GAL.

Effect of galanin on substance P- and vasoactive intestinal polypeptide-induced nociceptive trigemino-hypoglossal reflex in rats.

Substance P (SP), vasoactive intestinal polypeptide (VIP) and galanin (GAL), present in primary sensory neurons, are involved in transmission of nociceptive signaling from the peripheral to central nervous system. In this study we investigated the effect of GAL on SP-induced or VIP-induced evoked tongue jerks (ETJ) in response to noxious tooth pulp stimulation during perfusion of the cerebral ventricles with SP or VIP solutions. The experiments were carried out on rats under chloralose anesthesia. It was shown that both, SP and VIP, perfused through the cerebral ventricles enhanced the ETJ amplitude as compared with control, but the effect produced by SP was stronger. The intracerebroventricular perfusion of GAL 5 minutes before SP caused a dose-dependent inhibition of SP-induced ETJ, whereas GAL perfused through the cerebral ventricles 5 minutes before VIP did not reduce the excitatory effect of VIP on ETJ. These results indicate that the antinociceptive effect of GAL perfused through the cerebral ventricles, tested on the trigemino-hypoglossal reflex in rats, is specifically mediated by the SP-ergic system.

Effect of tooth pulp stimulation on oxytocin and vasopressin release into the cerebrospinal fluid and fluid perfusing the cerebral ventricles in rats.

OBJECTIVE: Stress- and pain-related stimuli cause a release of vasopressin (AVP) and oxytocin (OT) into the cerebrospinal fluid (CSF) and extracellular fluid of the brain in various animal species. The aim of the study was to investigate the effect of stimulation of the nociceptive afferent terminals in the tooth pulp on the release of AVP and OT into CSF in rats under chloralose anesthesia. METHODS: Cerebrospinal fluid was collected from the cerebellomedullary cistern and then 30-minute perfusions of the lateral cerebral ventricles with artificial cerebrospinal fluid (aCSF) were carried out. The perfusate was collected from the cerebellomedullary cistern at rest (control), during electric stimulation of the tooth pulp which induced nociceptive trigemino-hypoglossal reflex, and after stimulation. In the collected CSF and aCSF perfusates, AVP-like immunoreactivity (AVPLI) and OT-like immunoreactivity (OT-LI) were determined by radioimmunoassay (RIA). RESULTS: The concentrations of AVP-LI and OT-LI in CSF were found to reach 21 pg/ml and 67 pg/ml, respectively. Electric tooth pulp stimulation exerted no effect on AVP and OT release into the fluid perfusing the cerebral ventricles during stimulation. CONCLUSION: It was found that noxious stimulus from the tooth pulp is not a factor affecting significantly AVP and OT release into CSF.

Effect of cerebral ventricles perfusion with morphiceptin and Met-enkephalin on trigemino-hypoglossal reflex in rats.

Opioids administered by intracerebroventricular injections produce analgesic responses in rats. The present study was undertaken to investigate the effects of a highly selective mu-opioid receptor ligand morphiceptin on trigemino-hypoglossal reflex in rats. The analgesic effect of morphiceptin was compared with another opioid peptide, Met-enkephalin. With the experimental settings used in this study, we have demonstrated that both morphiceptin and Met-enkephalin show significant dose-dependent analgesic effects after i.c.v. administration in rats as assayed by trigemino-hypoglossal reflex test. The antinociceptive response to Met-enkephalin was short lasting and was observed 10 to 15 min after i.c.v. perfusion. Morphiceptin had a relatively longer duration of antinociceptive action, the effect was observed 20-50 min after i.c.v. perfusion. Neither morphiceptin nor Met-enkephalin produced antinociception after peripheral injections. The results of the present study indicate that both tested peptides act at mu-opioid receptors situated in the central nervous system. They also suggest that mu-opioid receptors present in the central nervous system are an important element of the trigemino-hypoglossal reflex arc. For that reason selective mu-opioid receptor ligands, like morphiceptin, inhibit the reflex more significantly.

Somatostatin analogs.

Somatostatin is a hypothalamic peptide hormone that inhibits the secretion of growth hormone, glucagon, insulin, gastrin and secretin, and also plays a role in neural transmission. Because of its wide range of possible clinical applications hundreds of somatostatin analogs have been synthesized and bioassayed to date. This review gives a historical perspective, summarizing approximately 30 years of research on somatostatin. The main focus is on the structure-activity relationships and conformational studies of the last generation of somatostatin agonists and their selectivity for five somatostatin receptor subtypes. Achievements in the synthesis of nonpeptide somatostatin analogs, as well as the first somatostatin antagonists, are also discussed. Finally, the use of a cyclic somatostatin scaffold to design ligands for other G-protein-coupled receptors, such as opioid and melanocortin receptors, is mentioned.

Synthesis and biological activity of highly potent heptapeptide analogs of somatostatin with C-terminal modifications.

OBJECTIVE: Structure-activity relationship studies of a series of new heptapeptide analogs of somatostatin with C-terminal modifications were performed. METHODS: New somatostatin analogs were synthesized by solid-phase method. The suppression of the release of growth hormone by the new analogs was assayed in vivo in rats, and the duration of action was investigated using growth hormone time-course assay. Growth hormone concentration in plasma samples was determined by RIA. RESULTS: The growth hormone release inhibitory activity of the new analogs was up to 50 times greater than that of somatostatin. Hydrophilic substitutions at the C-terminus seemed to be advantageous for potency. The most potent analog of the series, D-Phe-c[Cys-Phe-D-Trp-Lys-Thr-Cys]-NH-CH2-CH2-OH showed the most prolonged activity by inhibiting the release of growth hormone for at least 3 h. The analogs containing D-Phe or D-Tyr at the N-terminus were almost equipotent, which proves that the exocyclic N-terminal residue is not involved directly in the receptor recognition. CONCLUSIONS: New heptapeptide analogs of somatostatin with C-terminal modifications were more potent and longer acting than the native hormone.

Effect of cerebral ventricles perfusion with naloxone on trigemino-hypoglossal reflex in rats.

The goal of this study was to determine whether opioid receptor antagonist naloxone abolishes the influence of periaqueductal central gray (PAG) on nociceptive evoked tongue jerks (ETJ) -- a trigemino-hypoglossal reflex induced by tooth pulp stimulation. In rats under chloralose anesthesia three series of experiments were performed. In the first two groups perfusions of lateral ventricles-cerebellomedullary cistern with McIlwain-Rodnight's solution and naloxone were carried out. In group 3 naloxone was infused through a catheter through the jugular vein. The amplitudes of tongue jerks induced by tooth pulp stimulation were recorded during subsequent 10 min perfusions. Mean amplitude of tongue movements induced by tooth pulp stimulation was regarded as the indicator of the magnitude of trigemino-hypoglossal reflex. We observed that perfusion of the cerebral ventricles with naloxone (100 nmol/ml) increased the trigemino-hypoglossal reflex up to 143%. The amplitude of ETJ was significantly reduced during PAG stimulation with a train of electrical impulses. After obtaining a significant -- 93% -- inhibition of ETJ (7% of the control), naloxone (100 nmol/ml) was added to the perfusion fluid. This led to a significant increase of the reflex up to 68%. Infusion of naloxone through the jugular vein did not affect the reflex. The above results suggest that the inhibition of ETJ due to PAG stimulation is partially reversed by naloxone and mediated via interactions with endogenous opioid systems involved in modulation of nociception.

The effect of naloxone on trigemino-hypoglossal reflex inhibited by periaqueductal central gray stimulation in rats.

The aim of the study was to determine whether opioid receptor antagonist naloxone abolishes the influence of periaqueductal central gray (PAG) on nociceptive evoked tongue jerks (ETJ) - a trigemino-hypoglossal reflex induced by tooth pulp stimulation. In rats under chloralose anesthesia three subsequent series of perfusions of lateral ventricles - cerebellomedullary cistern with Mc Ilwain-Rodnight's solution, Met-enkaphalin (Enk-Met) and naloxone were carried out. The amplitudes of tongue jerks induced by tooth pulp stimulation were recorded during subsequent 10 min perfusions. Mean amplitude of tongue movements induced by tooth pulp stimulation was regarded as the indicator of the magnitude of trigemino-hypoglossal reflex. We observed that perfusion of the cerebral ventricles with Enk-Met (100 nmol/mL) inhibited the trigemino-hypoglossal reflex by 46%, whereas naloxone (100 nmol/mL), added to the solution perfusing the cerebral ventricles system, increased the reflex by 42%. The amplitude of ETJ was significantly reduced during PAG stimulation with a train of electrical impulses. After obtaining a significant 93% - inhibition of ETJ, naloxone (100 nmol/mL) was added to the perfusion fluid. This led to a significant increase of the reflex by 68%. The above results suggest that the inhibition of ETJ due to PAG stimulation is partially reversed by naloxone and mediated via interactions with endogenous opioid systems involved in modulation of nociception.

Comparison of antagonistic properties of substance P analogs, spantide I, II and III, on evoked tongue jerks in rats.

OBJECTIVE: To study and evaluate the effects of perfusion through cerebral ventricles with substance P (SP) and its analogs: spantide I, II and III on evoked tongue jerks (ETJ) in male rats. METHODS: During the perfusion, stimulation of the tooth pulp caused retractive movements of the stretched tongue, the amplitudes of which were recorded. The mean amplitudes of evoked tongue jerks (ETJ) recorded during each 10 min. period of perfusion with McIlwain-Rodnight's solution and solutions containing peptides were compared. RESULTS: Perfusion of cerebral ventricles with SP caused a significant increase in the mean amplitude of evoked tongue jerks. Spantide I caused a complete respiratory arrest in all of the examined animals, so its effect on the trigemino-hypoglossal reflex could not have been tested. Spantide II, in the first two minutes, induced a transient significant decrease in ETJ amplitude, followed by an increase in ETJ in the next 8 min. SP perfused after spantide II caused a further significant increase in ETJ, as compared with control. Perfusion of cerebral ventricles with spantide III caused a significant, dose-dependent decrease in ETJ. SP perfused after spantide III caused a smaller increase in ETJ than it was observed without spantide III. CONCLUSION: Spantide III was found to be a strong antagonist of SP in trigemino-hypoglossal reflex.

Stent implantation for aortic coarctation and recoarctation.

OBJECTIVE: To determine the early results of balloon expandable stent implantation for aortic coarctation or recoarctation. DESIGN: Prospective observational study. SETTING: Two paediatric cardiology tertiary referral centres. PATIENTS: 17 patients, median age 17 years (range 4.4 to 45) and median weight 61 kg (17 to 92). Six had native aortic coarctation and 11 had aortic recoarctation; 14 had upper limb systolic hypertension. Of those with recoarctation, eight had had at least one previous balloon dilatation attempt and two of these patients also had further surgical interventions. INTERVENTION: Balloon expandable Palmaz iliac stent implantation. MAIN OUTCOME MEASURES: Systolic pressures gradients, minimum aortic diameter, upper limb blood pressures, and incidence of aneurysm formation. RESULTS: 18 stents were implanted during 18 procedures in the 17 patients. Mean peak systolic pressure gradient fell from 26 mm Hg (95% confidence interval (CI), 21 to 31 mm Hg) before to 5 mm Hg (2 to 8 mm Hg) after stent implantation (p < 0.001), and mean minimum aortic diameter increased from 7 mm (95% CI, 6 to 8 mm) before to 11.3 mm (10 to 12.6 mm) after implantation (p < 0.001). Complications occurred in five patients (bleeding in two, stent migration in two, and aneurysm formation in one). Two patients remained borderline hypertensive and eight were receiving antihypertensive treatment at most recent assessment. CONCLUSIONS: Stent implantation for aortic recoarctation and native coarctation gives good immediate results. Careful follow up is necessary to evaluate complications and the long term effect on blood pressure.

Middle aortic syndrome treated by stent implantation.

OBJECTIVES: To determine outcome of stent implantation in patients with middle aortic syndrome. DESIGN: Prospective study, case series. SETTING: A tertiary paediatric cardiology centre in a children's hospital. PATIENTS: Five patients, aged 4 to 17 years (mean 11.4 years), with upper limb hypertension due to middle aortic syndrome. INTERVENTION: Stents were implanted in the mid/lower thoracic/upper abdominal aorta. MAIN OUTCOME MEASURE: Satisfactory deployment of stents and blood pressure control. RESULTS: In all patients, angiocardiography showed long segment stenosis in the mid or lower thoracic/upper abdominal aorta. The pressure gradient was between 40 and 90 mm Hg (mean 63.2 mm Hg). Seven Palmaz stents were implanted. Immediately after implantation, the gradient decreased to between 0 and 35 mm Hg (mean 13.6 mm Hg). Angiography showed a satisfactory result with widely patent stents in all. In one patient, thrombosis of the stent occurred six days after implantation. This was successfully treated with infusion of alteplase, further balloon dilatation, and implantation of a second stent overlapping the first, both dilated to 10 mm diameter. One patient had elective redilatation of the stent six months after implantation, with further reduction of the gradient from 35 mm Hg to 10 mm Hg. At the latest follow up between three and 20 months (mean 12.2 months) after stent implantation, in four patients blood pressure was better controlled with antihypertensive drugs. One patient was normotensive without drugs. Computed tomography showed no aneurysm formation in the region of the stents. CONCLUSIONS: Stent implantation is a preferable alternative to surgery in the treatment of patients with middle aortic syndrome and merits further evaluation.

Inhibition of tongue reflex in rats by tooth pulp stimulation during cerebral ventricle perfusion with (6-11) substance P analogs.

The effect of 12 C-terminal hexapeptide analogs of substance P perfused into the cerebral ventricles on the trigemino-hypoglossal reflex caused by incisor pulp stimulation in rats was investigated. A substitution of the L-isomer by D at position 6, 7, or 8 of the substance P analogs used in this study caused the most pronounced inhibition of the trigemino-hypoglossal reflex. A correlation between the degree of inhibition of the reflex and concentration of the peptide used was observed.