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Genetic polymorphisms have been shown to affect opioid requirement for pain relief. However, true genetic effect is often difficult to assess due to underlying pain conditions and placebo effects. The goal of this study was to understand how common polymorphisms affect opioid effects while controlling for these factors. A randomized, double-blind, placebo-controlled study was implemented to assess how opioid effects are modulated by COMT (rs6269, rs4633, rs4848, rs4680), OPRM1 (A118G), and OPRK1 (rs1051660, rs702764, rs16918875). One hundred and eight healthy subjects underwent experimental pain testing before and after morphine, butorphanol, and placebo (saline). Association analysis was performed between polymorphisms/haplotypes and opioid response, while correcting for race, gender, placebo effects, and multiple comparisons. Pressure pain was significantly associated with rs6269 and rs4633 following butorphanol. The AA genotype of rs4680 or A_T_C_A/ A_T_C_A (rs6269_rs4633_ rs4818_rs4680) diplotype of COMT, combined with the AG genotype of OPRM1 A118G, showed significantly increased pressure pain threshold from butorphanol. Opioid effects on pressure, ischemic, heat pain, and side effects were nominally associated with several SNPs and haplotypes. Effects were often present in one opioid but not the other. This indicates that these polymorphisms affect pain relief from opioids, and that their effects are opioid and pain modality specific.
Learn More >Opioid Dose and Benzodiazepine Use Among Commercially Insured Individuals on Chronic Opioid Therapy.
To examine morphine milligram equivalent (MME) trends, use of concurrent opioids and benzodiazepines, and opioid-related emergency department (ED) visits or hospitalizations in a national cohort of patients on chronic opioid therapy.
Learn More >Pruritus, a common symptom of psoriasis, negatively impacts quality of life; however, treatment of lesional skin does not consistently alleviate psoriatic itch.
Learn More >Few migraine preventive agents have been assessed in a pediatric population. We evaluated the safety and efficacy of cinnarizine and sodium valproate for migraine prophylaxis in children and adolescents.
Learn More >Non-bacterial prostatitis is an inflammatory disease that is difficult to treat. Oligonucleotide aptamers are well known for their stability and flexibility in conjugating various inflammatory molecules. In this study, we investigated the effects of inflammatory cytokine-targeting aptamers (ICTA), putative neutralizers of TNF-alpha and IL-1 beta activation, on local carrageenan-induced prostate inflammation, allodynia, and hyperalgesia in rats. In vitro evaluation confirmed the binding capability of ICTA. Intraprostatic injection of carrageenan or control vehicle was performed in six-week-old rats, and ICTA (150 µg) or vehicle was administered in the prostate along with carrageenan injection. The von Frey filament test was performed to determine mechanical allodynia, and prostate inflammation was examined seven days after drug administration. Local carrageenan administration resulted in a reduction of the tactile threshold. The levels of mononuclear cell infiltration, pro-inflammatory cytokine interleukin-1 beta (b), caspase-1 (casp-1), and Nucleotide-binding oligomerization domain, Leucine rich Repeat and Pyrin domain containing proteins 1 and 3 (NALP1 and NALP3) in the prostate of rats were increased seven days after carrageenan injection. Treatment with ICTA significantly attenuated the carrageenan-induced hyperalgesia and reduced the elevated levels of proteins including TNF-a and IL-1b in the rats. Apoptosis markers, B-cell lymphoma 2-associated X protein (Bax) and caspase-3, were elevated in ICTA-treated Chronic pelvic pain syndrome (CPPS) rats. These results suggest that ICTA provides protection against local carrageenan-induced enhanced pain sensitivity, and that the neutralization of proinflammatory cytokines may result in inflammatory cell apoptosis.
Learn More >Regulators of G protein signaling (RGS) are multifunctional proteins expressed in peripheral and neuronal cells, playing critical roles in development, physiological processes, and pharmacological responses. RGS proteins primarily act as GTPase accelerators for activated Gα subunits of G-protein coupled receptors (GPCRs), but they may also modulate signal transduction by several other mechanisms. Over the last two decades, preclinical work identified members of the RGS family with unique and critical roles in intracellular responses to drugs of abuse. New information has emerged on the mechanisms by which RGS proteins modulate the efficacy of opioid analgesics in a brain region- and agonist-selective fashion. There has also been progress in the understanding of the protein complexes and signal transduction pathways regulated by RGS proteins in addiction and analgesia circuits. In this review, we summarize findings on the mechanisms by which RGS proteins modulate functional responses to opioids in models of analgesia and addiction. We also discuss reports on the regulation and function of RGS proteins in models of psychostimulant addiction. Using information from preclinical studies performed over the last 20 years, we highlight the diverse mechanisms by which RGS protein complexes control plasticity in response to opioid and psychostimulant drug exposure; we further discuss how the understanding of these pathways may lead to new opportunities for therapeutic interventions in G protein pathways SIGNIFICANCE STATEMENT: RGS proteins are signal transduction modulators, expressed widely in various tissues, including brain regions mediating addiction and analgesia. Evidence from preclinical work suggests that members of the RGS family act by unique mechanisms in specific brain regions to control drug-induced plasticity. This review highlights interesting findings on the regulation and function of RGS proteins in models of analgesia and addiction.
Learn More >The Patient Registry of Intrathecal Ziconotide Management evaluated the long-term effectiveness and safety of intrathecal ziconotide.
Learn More >Delta opioid receptor (δ-receptor) agonists produce antihyperalgesia, antidepressant-like effects, and convulsions in animal models. However, the role of agonist efficacy in generating different δ-receptor-mediated behaviors has not been thoroughly investigated. To this end, efficacy requirements for δ-receptor-mediated antihyperalgesia, antidepressant-like effects, and convulsions were evaluated by comparing the effects of the partial agonist BU48 and the full agonist SNC80 as well as changes in the potency of SNC80 following δ-receptor elimination. Antihyperalgesia was measured in a nitroglycerin-induced thermal hyperalgesia assay. An antidepressant-like effect was evaluated in the forced swim test. Mice were observed for convulsions after treatment with SNC80 or the δ-opioid receptor partial agonist BU48. Ligand-induced G protein activation was measured by [35S]GTPγS binding in mouse forebrain tissue and δ-receptor number was measured by [3H]DPDPE saturation binding. BU48 produced antidepressant-like effects and convulsions but antagonized SNC80-induced antihyperalgesia. The potency of SNC80 was shifted to the right in δ-receptor heterozygous knockout mice and 5'-NTII treated mice, and the magnitude of potency shift differed across assays with the largest shift occurring in the thermal hyperalgesia assay followed by the forced swim test, and then convulsion observation. NTI antagonized these SNC80-induced behaviors with similar potencies suggesting that these effects are mediated by the same type of δ-receptor. These data suggest that δ-receptor-mediated behaviors display a rank order of efficacy requirement with antihyperalgesia having the highest requirement, followed by antidepressant-like effects and then convulsions. These findings further our understanding of the pharmacological mechanisms mediating the in vivo effects of δ-opioid receptor agonists. SIGNIFICANCE STATEMENT: Delta opioid receptor (δ-receptor) agonists produce antihyperalgesia, antidepressant-like effects, and convulsions in animal models. This study evaluates pharmacological properties, specifically the role of agonist efficacy and receptor reserve, underlying these δ-receptor-mediated behaviors. These data suggest that δ-receptor-mediated behaviors display a rank order of efficacy requirement with antihyperalgesia having the highest requirement, followed by antidepressant-like effects and then convulsions.
Learn More >Oxaliplatin-induced peripheral neurotoxicity (OIPN) is a severe and potentially permanent side effect of cancer treatment affecting the majority of oxaliplatin-treated patients, mostly with the onset of acute symptoms, but also with the establishment of a chronic sensory loss that is supposed to be due to dorsal root ganglia neuron damage. The pathogenesis of acute as well as chronic OIPN is still not completely known, and this is a limitation in the identification of effective strategies to prevent or limit their occurrence. Despite intense investigation at the preclinical and clinical levels, no treatment can be suggested for the prevention of OIPN, and only limited evidence for the efficacy of duloxetine in the treatment setting has been provided. In this review, ongoing neuroprotection clinical trials in oxaliplatin-treated patients will be analyzed with particular attention paid to the hypothesis leading to the study, to the trial strengths and weaknesses, and to the outcome measures proposed to test the efficacy of the therapeutic approach. It can be concluded that 1) prevention and treatment of OIPN still remains an important and unmet clinical need, 2) further, high-quality research is mandatory in order to achieve reliable and effective results, and 3) dose and schedule modification of OHP-based chemotherapy is currently the most effective approach to limit the severity of OIPN.
Learn More >Opioids are effective analgesics in the management of severe pain. However, tolerance, leading to dose escalation and adverse effects are significant limiting factors in their use. The role of peripheral opioid receptors in analgesia has been discussed especially under inflammatory conditions. The results from pharmacological and conditional knockout studies together do not provide a clear picture of the contribution of peripheral opioid receptors on antinociceptive tolerance and this needs to be evaluated. Therefore, we studied whether the peripherally restricted opioid receptor antagonist, methylnaltrexone (MNTX), could prevent morphine tolerance without attenuating the antinociceptive effect of morphine. Male Sprague-Dawley rats were treated for 7 days with increasing subcutaneous doses of morphine (5-30 mg/kg) and were coadministered saline, MNTX (0.5 or 2 mg/kg), or naltrexone (NTX; 2 mg/kg). Nociception was assessed with tail-flick, hotplate, and von Frey tests. Morphine, MNTX, and NTX concentrations in the plasma, brain, and spinal cord were measured by liquid chromatography-tandem mass spectrometry. In acute coadministration, NTX, but not MNTX, abolished the acute antinociceptive effects of morphine in all nociceptive tests. The antinociceptive tolerance after repeated morphine administration was also prevented by NTX but not by MNTX. MNTX penetrated to the spinal cord and the brain to some extent after repeated administration. The results do not support the use of MNTX for preventing opioid tolerance and also suggest that morphine tolerance is mediated by central rather than peripheral opioid receptors in the rat.
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