Melik Seyrek

Topical cannabinoid enhances topical morphine antinociception

Opioids and cannabinoids produce antinociception through both spinal and supraspinal action. Both opioids and cannabinoids also have important peripheral action. Many previous studies indicate that systemically administered cannabinoids enhance antinociceptive properties of opioids. Experiments were conducted to test the hypothesis that topical cannabinoids would enhance the topical antinociceptive effects of morphine. Antinociception was measured in the radiant tail‐flick test after immersion of the tail of mice into a solution of dimethyl sulfoxide (DMSO) containing WIN 55, 212‐2, a cannabinoid agonist and morphine, an opioid agonist. Morphine and WIN 55, 212‐2 produce time dependent topical analgesic effects limited to the portion of the tail exposed to drugs. WIN 55, 212‐2 had a potency lower than that of morphine. The topical antinociceptive effects of WIN 55, 212‐2 were blocked by systemic pretreatment of cannabinoid CB1 receptor selective antagonist, AM 251. This suggests that topical antinociceptive effects of WIN 55, 212‐2 involve CB1 receptors. Combination of topical WIN 55, 212‐2 with topical morphine yielded significantly greater analgesic effects than that of topical morphine alone. The ability of the CB1 receptor antagonist AM 251 to antagonize the enhancement of antinociception of morphine by WIN 55, 212‐2 indicates that WIN 55, 212‐2 acts through a CB1 receptor to enhance the potency of topical morphine. Additionally, spinally administered ineffective doses of WIN 55, 212‐2 potentiated the antinociceptive effects of topical morphine. These results demonstrate an antinociceptive interaction between topical opioids with topical, and spinal cannabinoids. These observations are significant in using of topical combination of cannabinoid and morphine in the management of pain.

The Vasodilator Effect of Testosterone on the Human Internal Spermatic Vein and its Relation to Varicocele Grade

PURPOSEnSeveral animal and human studies in vivo and in vitro indicate that testosterone has vasodilatory effects on different vessels. However, the effect of testosterone on the internal spermatic vein is not clear. In addition, the role of testosterone in the pathophysiology of varicocele is not established. We investigated the effect of testosterone on the internal spermatic vein in vitro in patients with varicocele and analyzed its relation to varicocele grade.nnnMATERIALS AND METHODSnIsolated internal spermatic veins were collected from patients who underwent varicocelectomy and orchiectomy. The preparations (3 to 4 mm rings) were mounted in an organ bath containing 10 ml Krebs-Henseleit solution on an L-shaped brace for tension measurement along the former circumferential axis. Changes in venous tension in the presence of testosterone (0.1 to 300 microM) were recorded isometrically by a force displacement transducer.nnnRESULTSnCumulative concentrations of testosterone (0.1 to 300 microM) elicited concentration dependent relaxation of 45 mM KCl induced active tone in the internal spermatic vein (mean +/- SEM 60.97% +/- 5.05% of the KCl induced contraction). Relaxation to testosterone (1 to 300 microM) was significantly higher in 5 cases of grades 0 and 1 varicocele than in 15 of grades 2 and 3 varicocele (maximum relaxation response 78.58% +/- 8.25% vs 55.10% +/- 5.3% of the KCl induced contraction).nnnCONCLUSIONSnTo our knowledge the current report is the first to describe testosterone induced relaxation of the human internal spermatic vein. The vasodilatory effect of testosterone on the human internal spermatic vein decreases in high grade varicoceles.

Elevated serum neopterin levels in acetaminophen-induced liver injury.

Neopterin is synthesized in macrophage/Kupffer cells by interferon-gamma and other cytokines. This study aimed to evaluate the utility of using neopterin as a biomarker of acetaminophen (APAP)-induced liver injury. Wistar rats, randomly divided into two groups (APAP and normal), received APAP (1.0 g/kg) and distilled water, respectively, by gastric tube. The APAP group had a higher degree of liver necrosis than the control group. The APAP group also had significantly higher serum neopterin levels than the normal group. Serum neopterin levels correlated with serum AST, ALT activities, and degree of necrosis. This study demonstrates the preclinical utility of neopterin as a biomarker for the animal model of APAP-induced liver injury. Further research studies are required to determine the preclinical opportunities of using neopterin as a marker of APAP-induced liver injury.

Interaction Between Dexmedetomidine and α-Adrenergic Receptors: Emphasis on Vascular Actions

p Dexmedetomidine (DEX) is a new methylol derivative with high affinity to 2-adrenergic receptors. It causes analgesia and sympatholysis, and has sedative, anxiolytic, and hypnotic effects. The use of DEX and its affinity to 2-adrenergic eceptors in the body should not only be limited to sedation and nesthesia, because 2-adrenergic receptors are scattered hroughout the body. In 1948, Ahlquist et al1 first reported and subtypes of adrenergic receptors that were activated by noradrenalin, the mediator of sympathetic nervous system stimulation in mammals. In light of this preliminary report, numerous studies were performed on this topic and, in 1973, 1 and 2 subtypes of -adrenergic receptors were determined.2 In subsequent investigations, gene studies were developed, and 3 subtypes, called aA, 1B, and 1c, or 1-adrenergic receptors2 and 4 subtypes, called 2A, 2B, 2C, and 2D, for 2-adrenergic receptors were isolated.3,4 Studies perormed on isolated organ samples from several experimental anmals showed that both subtypes of -adrenergic receptors are present in postsynaptic membranes in many animal species, including rabbits and guinea pigs; 1-adrenergic receptors are domnant.5 In contrast, 2-adrenergic receptors were reported to be enser only in a number of tissues, such as human saphenous vein6 and femoral vein tissue.7 Experimental findings show that localization of -adrenergic receptor subtypes can differ among species nd vessel segments, so the responses that occur after activation of hese receptors vary.

The Histopathologic, Pharmacologic and Urodynamic Results of Mesenchymal Stem Cell’s Injection into the Decompensated Rabbit’s Bladder

ObjectivesWe researched the survival of bone marrow-derived mesenchymal stem cells (MSCs) and the results of MSCs’ injected into decompensated bladders in a rabbit model.MethodsPartial bladder neck obstruction (PBNO) and subsequent decompensation of the bladder was achieved by wrapping the bladder neck with autologous rectus fascia. In the first aspect of the experiment 18 rabbits underwent MSC injection into the decompensated bladder to prove the survivability of injected MSCs. For this purpose MSCs were isolated, transfected with Green Fluorescent Protein (GFP), and injected into the detrusor layer. Once viability was assessed in the first phase, an additional 10 rabbits underwent PBNO in the second phase. Five of these animals underwent subsequent MSC injection (group 3, stem cell) and 5 did not (group 2, obstruction). Both groups were compared to 5 controls (group 1). Urodynamics were performed in all groups. After the animals were sacrificed the groups were compared via morphometric analysis, contractile response to carbachol and KCl, and muscarinic receptor type analysis.ResultsOn morphometric analysis, collagenous area rates were 43, 53 and 37xa0% in group 1, 2 and 3, respectively. There was no statistically significant difference between groups in terms of bladder weight, bladder capacity and vesical pressure. The contractile effects of KCl and muscarinic agonist carbachol were significantly higher in groups 1 and 3 than group 2. The response to carbachol was antagonized by muscarinic M1 and M3 receptor antagonist pirenzepine and abolished by muscarinic M3 receptor antagonist 4-DAMP in all groups.ConclusionsThe injection of MSCs decreased the collagenous area, increased detrusor contractility. Functional M3 receptors were also expressed in MSCs-injected bladder smooth muscle as well as in control group.

Testosterone Relaxes Human Internal Spermatic Vein Through Potassium Channel Opening Action

OBJECTIVESnTo investigate the relation of testosterone-induced relaxation with smooth muscle K+ channels in human internal spermatic veins. Testosterone induces relaxation in human isolated internal spermatic veins, and this effect decreases in high-grade varicocele (recently reported).nnnMETHODSnThe responses of isolated internal spermatic veins from patients with varicocele were recorded isometrically using a force displacement transducer. After contracting the venous rings with 45 mM KCl, relaxation with testosterone (0.1-300 μM) was recorded in the absence or presence of large conductance calcium-activated K+ channel and the voltage-sensitive K+ channel inhibitor tetraethylammonium, adenosine triphosphate-sensitive K+ channel inhibitor glibenclamide, voltage-dependent inward rectifier K+ channel inhibitor barium chloride, and voltage-sensitive K+ channel inhibitor 4-aminopyridine.nnnRESULTSnTestosterone induced relaxation in human isolated internal spermatic veins in the absence of inhibitors (maximal effect 52.88±6.72, n=24). Although tetraethylammonium, barium chloride, and 4-aminopyridine did not alter the testosterone-induced relaxant responses, GLI inhibited these responses.nnnCONCLUSIONSnThese results have demonstrated that testosterone induces relaxation in human isolated internal spermatic veins of patients with varicocele by way of adenosine triphosphate-sensitive K+ channels.

The histopathological and pharmacodynamic effects of intradetrusor decorin injected in a rabbit partial bladder outlet obstruction model

Purpose To evaluate whether or not the bladder function can be protected by supporting the detrusor with decorin levels during the fibrotic process.MethodsForty-two male rabbits were divided into three main groups, partial bladder outlet obstruction (pBOO) group, pBOOxa0+xa0intradetrusor decorin-injected (IDI) group and control group. Both pBOO and pBOOxa0+xa0IDI groups were divided into three subgroups according to the killing schedule. Histopathological, immunohistochemical and pharmacodynamics studies were performed for the evaluation of fibrotic process and tissue characteristics.ResultsHistopathological evaluation revealed statistically significant high fibrosis levels for both pBOO and pBOOxa0+xa0IDI groups when compared with control. Strikingly the antifibrotic effect of decorin was significant on 2nd, 4th and 8th week and increased as time passed. Immunohistochemical analysis was revealed high expressions of anti-TGF-β1 and decorin levels in all pBOOxa0+xa0IDI groups. Pharmacodynamical results were also revealed better contraction responses in favor of 2nd, 4th and 8th week groups of pBOOxa0+xa0IDI groups, when compared with pBOO groups. In addition, the contraction responses against the depolarizer agent KCl were increased in the three decorin-administrated groups.ConclusionOur study demonstrates the antifibrotic effects of decorin on bladder fibrosis. Strikingly, this antifibrotic effect is shown in histopathological, immunohistochemical and pharmacodynamics studies. Although further studies are warranted to make more decisive inferences regarding its clinical use, our study has the proper pride to be the first step of this time course.