No abstract

Alpha 2 agonists have been shown to have opioid-sparing effects, but can cause hypotension and bradycardia and must be taken into consideration when administered. Acetaminophen is commonly used in a multimodal approach, with recent evidence lacking for the use of IV over oral formulations in patients able to take medications by mouth. Studies involving gabapentinoids have been mixed with some showing benefit; however, future large randomized controlled trials are needed. Ketamine is known to have powerful analgesic effects and, when combined with magnesium and other agents, may have a synergistic effect. Dexamethasone reduces postoperative nausea and vomiting and has been demonstrated to be an effective adjunct in multimodal analgesia. The serotonin-norepinephrine reuptake inhibitor, duloxetine, is a novel agent, but studies are limited and further evidence is needed. Overall, a multimodal analgesic approach should be used when treating postoperative pain, as it can potentially reduce side effects and provide the benefit of treating pain through different cellular pathways.

3,4-Methylenedioxymethamphetamine (MDMA, “Ecstasy”) is a potent psychedelic drug inducing euphoria and hyper-sociability in humans, as well as hyperactivity and anxiety in rodents. Adult zebrafish (Danio rerio) have become a widely used species in neurobehavioral research. Here, we explore the effects of a wide range (0.25–120 mg/L) of acute MDMA doses on zebrafish behavior in the novel tank test. While MDMA was inactive at lower doses (0.25–10 mg/L), higher doses reduced bottom swimming and immobility (40–120 mg/L) and impaired intra-session habituation (10–120 mg/L). MDMA also elevated brain c-fos expression, collectively confirming the utility of zebrafish models for screening of hallucinogenic compounds.

Introduction Soluble guanylate cyclase (sGC) is the receptor for nitric oxide (NO) and in pathophysiologic conditions where NO formation or bioavailability is impaired, erectile dysfunction (ED) occurs. Aim The aim of this study was to investigate erectile responses to the sGC stimulator BAY 41-8543 in physiologic and pathophysiologic conditions. Methods Increases in intracavernosal pressure (ICP) in response to intracavernosal (ic) injections of BAY 41-8543 were investigated in the anesthetized rat. Main Outcome Measures Increases in ICP/MAP in response to ic injections of BAY 41-8543 and the interaction of BAY 41-8543 with exogenous and endogenously released NO were investigated and the effect of the sGC stimulator on cavernosal nerve injury was assessed. The mechanism of the increase in ICP/MAP in response to ic injection of acetylcholine was investigated. Results The ic injections of BAY 41-8543 increased ICP/MAP and the duration of the response. BAY 41-8543 was less potent than SNP and ic injections of BAY 41-8543 and SNP produced a larger response than the algebraic sum of responses to either agent alone. Simultaneous ic injection of BAY 41-8543 and cavernosal nerve stimulation produced a greater response than either intervention alone. Atropine and cavernosal nerve crush injury decreased the response to nerve stimulation and ic injection of BAY 41-8543 restored the response. Conclusion These data show that BAY 41-8543 has significant erectile activity and can synergize with exogenous and endogenously released NO. This study shows that atropine and nerve crush attenuate the response to cavernosal nerve stimulation and that BAY 41-8543 can restore the response. The results with atropine, L-NAME and hexamethonium indicate that the response to ic injection of acetylcholine is mediated by muscarinic receptors and the release of NO with no significant role for nicotinic receptors. These results suggest that BAY 41-8543 would be useful in the treatment of ED.

Objectives To investigate the effects of the selective Rho-kinase (ROCK) inhibitor azaindole-1 on erectile function under physiologic and pathophysiologic conditions in the rat. Methods The effect of intracavernosal (i.c.) injections of azaindole-1 on change in ICP, ICP/MAP, AUC, and response duration were investigated in the anesthetized rat under control conditions and when NANC neurotransmission and cholinergic function or sGC were inhibited or after cavernosal nerve crush injury. Results The i.c. injections of azaindole-1 produced dose-related increases in ICP/MAP and AUC that were long lasting at the highest doses studied when compared with the prototypical ROCK-inhibitor fasudil. Erectile responses were not altered by 7-NI and atropine in doses that reduced the response to cavernosal nerve stimulation by 86%, indicating that they were independent of NO release by cavernosal nerves or activation of muscarinic receptors in the corpora cavernosa. Erectile responses to azaindole-1 were not altered by the sGC inhibitor ODQ in a dose that attenuated responses to the NO donor SNP indicating that they were independent of an action on sGC. The erectile response to ic injections of azaindole-1 or Y-27632 which was reported to be NO/cGMP- dependent were not attenuated after cavernosal nerve crush injury. Conclusions The present studies indicate azaindole-1 has long lasting erectile activity that is independent of NO release, muscarinic receptor, or sGC activation or the integrity of the cavernosal nerves.