Search Results (101)

Topiramate evokes pharmacological activity via a blockade of voltage-dependent sodium channels, reduction in glutamate release, inhibition of AMPA receptors and kainate receptors, and potentiation of GABAergic neurotransmission. Therefore, it is used not only as an antiseizure drug but is also effective in migraine prophylaxis, cluster headaches, neuropathic pain, and alcohol dependence. The aim of this study was to investigate the effect of topiramate in morphine dependence in mice, particularly in terms of morphine tolerance, morphine withdrawal signs, and morphine sensitization. In these experiments, topiramate was administered both acutely and chronically. Topiramate significantly reduced the morphine tolerance in the hot-plate test and attenuated naloxone-induced morphine withdrawal signs. Its effect on morphine sensitization to the locomotor activity of mice was poor. The obtained results showed that topiramate might be an effective drug for reducing the physical symptoms of morphine dependence. Full article

Wounding triggers complex secondary metabolic pathways in plants, including benzylisoquinoline alkaloid (BIA) biosynthesis in opium poppy (Papaver somniferum L.). This study explores transcriptional and metabolic responses to wounding and methyl jasmonate (MeJA) treatment, focusing on BIA biosynthesis and regulatory mechanisms. Real-time expression analysis revealed significant up-regulation of transcripts in the (S)-reticuline and papaverine biosynthetic pathway, while the noscapine pathway was suppressed. The morphinan pathway also showed transcriptional activation, except in the case of codeinone reductase (COR), which remained unresponsive to both wounding and MeJA, suggesting a partially uncoupled mechanism. Metabolite profiling using HPLC-MS demonstrated a rapid accumulation of morphine post wounding, further supporting the hypothesis of independent regulatory control over COR. The role of phospholipase C (PLC) in modulating wound-induced BIA accumulation was investigated, revealing that PLC inhibition reduced morphine production and suppressed COR expression. These findings highlight the importance of phospholipid-dependent signalling in activating morphine biosynthesis, potentially at the expense of other BIAs. This study provides insights into plant stress responses and suggests strategies for enhancing BIA production through targeted interventions, offering potential applications in improving alkaloid yield. Full article

N6-methyladenosine (m⁶A) is one of the most prevalent methylated modifications of mRNA in eukaryotes. This reversible alteration can directly or indirectly influence biological functions, including RNA degradation, translation, and splicing. This study investigates the impact of chronic morphine administration and varying withdrawal durations (1 day, 1 week, 4 weeks, and 12 weeks) on the m⁶A modification levels in brain regions critical to addiction development and persistence. Our findings indicate that in the prefrontal cortex, the m⁶A levels and METTL3 expression decrease, accompanied by an increase in FTO and ALKBH5 expression, followed by fluctuating, but statistically insignificant changes in methylation-regulating enzymes over prolonged withdrawal. In the striatum, reductions in m⁶A levels and METTL3 expression are observed at 4 weeks of withdrawal, preceded by non-significant fluctuations in enzyme expression and the m⁶A modification levels. In contrast, no changes in the m⁶A modification levels or the expression of related enzymes are detected in the hippocampus and the cerebellum. Our data suggest that m⁶A modification and its regulatory enzymes undergo region-specific and time-dependent changes in response to chronic morphine exposure and subsequent withdrawal. Full article

Recently, an old drug, disulfiram, has been shown to reduce cocaine intake by inhibiting dopamine beta (β)-hydroxylase. Its effectiveness was also reported in opioid treatment, as disulfiram attenuated morphine-induced tolerance and dependence. A similar mechanism of action was evident in a selective inhibitor of DβH, nepicastat, particularly in the aspect of cocaine-seeking behavior. Hence, the objective of this study was to verify whether or not nepicastat reproduces disulfiram activity in pain reduction. Moreover, determination of its likely biological effects resulting from interactions with targets other than DβH has been given, in particular acetylcholinesterase. As was found, nepicastat was characterized by the absence of desired antinociceptive activity, though its co-administration with morphine resulted in a dose- and time-dependent enhancement of morphine-induced analgesic effect and attenuation of tolerance. Similarly, nepicastat was found to manifest antimicrobial potency against selected bacterial strains, although the effect was found to be weak. Intriguingly, this compound interacted with acetylcholinesterase through inhibition of its activity. These results clearly indicate nepicastat as a potent molecule that exhibits various biological effects. This, in turn, suggests its possible application in pathological conditions that still require effective treatment. Full article

HIV-associated neurocognitive disorders are prevalent despite antiretroviral intervention. Some HIV virotoxins, such as the trans-activator of transcription (Tat), are not targeted by antiretrovirals, and their neurotoxic actions may be exacerbated by opioids. Both Tat and morphine disrupt mitochondrial function, which may promote neurotoxicity, but the mechanisms are poorly understood. Herein, we assess the capacity of HIV Tat and morphine to alter the fundamental ability of mitochondria to generate and transfer energy along the electron transport chain (ETC). We find that exposure to Tat inhibits mitochondrial respiration driven by ETC complexes I or II in a concentration-dependent manner. Findings were consistent across models of permeabilized neuroblastoma cells, murine-derived mitoplasts, and mitochondria derived from mice exposed to Tat in vivo. In cell culture models, Tat promoted Ca²⁺ influx and the generation of cytosolic reactive oxygen species (ROS). Acute exposure to morphine exerted no effect on mitochondrial respiration, but morphine modestly offset Tat-mediated effects on complex I and some effects for the generation of ROS. Morphine did not exert any protective effects when acutely administered in vivo. The mitoprotective steroid, allopregnanolone (AlloP), increased mitochondrial respiration in neuroblastoma cells (complex I) or mitoplasts (complex II) and attenuated Tat-mediated impairment of complexes I and II in neuroblastoma cells or mice exposed to Tat in vivo. AlloP further attenuated Tat-mediated intracellular Ca²⁺ influx and cytosolic ROS production. Taken together, these results suggest that HIV Tat compromises mitochondrial function through the impairment of respiratory complexes I and II and that physiological AlloP may exert protective effects. Full article

Background: Spinal anesthesia is considered the method of choice for elective cesarean sections; however, it is not without maternal–fetal risks. Materials and Methods: This study compared the effects on maternal hemodynamics of intrathecal administration of fentanyl or morphine in parturients undergoing spinal anesthesia with 0.5% hyperbaric bupivacaine, with doses varied between 7.5 and 11 mg, depending on the patient’s height. Data from a cohort of 170 parturients were analyzed. The administered doses were intrathecal morphine at 0.1 mL (100 µg, solution of 1 mg/mL) or fentanyl at 0.25 mL (25 µg, solution of 50 µg/mL). This study included 80 patients in the fentanyl (F) group and 90 in the morphine (M) group. Results: Group F showed significantly higher post-intervention systolic blood pressure values than group M (95.30 ± 12.99 mmHg vs. 90.58 ± 14.75 mmHg, p = 0.032). The incidence of vomiting was significantly less frequent in group F compared to group M (1, 1.3% vs. 10, 11.1%, p = 0.011). The total dose of ephedrine required for hypotension correction was significantly lower in the F group (12.75 ± 13.26 mg vs. 17.72 ± 16.73 mg, p = 0.035). Conclusions: The addition of fentanyl as an adjuvant alongside the local anesthetic in cesarean section is associated with enhanced hemodynamic stability compared to morphine, requiring lower doses of ephedrine and contributing to increased patient safety during elective cesarean surgery. Full article

The neurological effects of opium were first described over 8000 years ago. Morphine was isolated in 1803 and by the mid-1800s had become both a pain-relieving blessing and an addictive curse. As part of the crusade to identify safer and more reliable alternatives to morphine, dezocine (Dalgan^®) was marketed in the US in 1986. Its use was discontinued in the US in 2011 without revealing the reasons, but it remains one of the most widely used analgesic agents in China today. Dezocine’s unique pharmacology makes it an effective analgesic with limited opioid-associated side effects and little or no reported potential for dependence and addiction. In addition, dezocine’s blocking effect on serotonin and norepinephrine transporters recommends its further exploration as a potential treatment for various chronic and neuropathic pain conditions. Most recently, data suggest that dezocine might represent a viable treatment for addiction management. This report focuses on the data supporting dezocine’s non-addictive profile and its potential use to treat opioid addiction and withdrawal, as well as recent efforts to generate formulations of dezocine that support sub-chronic and chronic dosing. Full article

Background/Objectives: Opium consumption was recently classified by the International Agency for Research on Cancer (IARC) monograph as carcinogenic to humans based on strong evidence for cancers of the larynx, lung, and urinary bladder, and limited evidence for cancers of the oesophagus, stomach, pancreas, and pharynx. This poses the question of a potential pro-cancer effect of pharmaceutical opioid analgesics. In vitro studies employing a variety of experimental conditions suggest that opioid alkaloids have proliferative or antiproliferative effects. We set out to reconcile this discrepancy and explore the hypothesis that opioids promote cancer cell proliferation in an organ-dependent fashion. Methods: Using strictly controlled conditions, we tested the effect of morphine on the proliferation of a series of human cancer cell lines isolated from organs where cancer risk was linked causally to opium consumption in human studies (i.e., lung, bladder, and larynx), or control organs where no link between cancer risk and opium consumption has been reported in human studies (i.e., breast, colon, prostate). Results: Our results showed a minimal effect on proliferation on any cell line and no trend supporting an organ-specific effect of morphine. Conclusions: This argues against a direct effect of opioids on tumour cell proliferation to support their organ-specific effect. Full article

Opioid-seeking behaviors depend on glutamatergic plasticity in the nucleus accumbens core (NAcc). Here we investigated whether the behavioral and synaptic effects of opioids are influenced by acid-sensing ion channel 1A (ASIC1A). We tested the effects of ASIC1A on responses to several opioids and found that Asic1a^−/− mice had elevated behavioral responses to acute opioid administration as well as opioid seeking behavior in conditioned place preference (CPP). Region-restricted restoration of ASIC1A in NAcc was sufficient to reduce opioid CPP, suggesting NAcc is an important site of action. We next tested the effects of oxycodone withdrawal on dendritic spines in NAcc. We found effects of oxycodone and ASIC1A that contrasted with changes previously described following cocaine withdrawal. Finally, we examined α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated and N-methyl-D-aspartic acid (NMDA) receptor-mediated synaptic currents in NAcc. Oxycodone withdrawal, like morphine withdrawal, increased the AMPAR/NMDAR ratio in Asic1a^+/+ mice, whereas oxycodone withdrawal reduced the AMPAR/NMDAR ratio in Asic1a^−/− mice. A single dose of oxycodone was sufficient to induce this paradoxical effect in Asic1a^−/− mice, suggesting an increased sensitivity to oxycodone. We conclude that ASIC1A plays an important role in the behavioral and synaptic effects of opioids and may constitute a potential future target for developing novel therapies. Full article

The use of cerebrospinal fluid (CSF) in post-mortem (PM) toxicological analysis is an under-addressed topic, likely due to the technical complexity of the collection of a proper sample. However, it is a matrix of significant interest since it has similar chemical and physical properties to the blood and it is less exposed to risks like PM redistribution and diffusion due to its anatomical location. This study aimed to validate a sensitive analytical method for the quantification of drugs of abuse and their metabolites (i.e., cocaine, ketamine, amphetamine, MDPV, 6-monoacetylmorphine, morphine, codeine, and methadone) through liquid chromatography–tandem mass spectrometry (LC-MS/MS). CSF was collected through ventricular puncture, and 200 µL was deproteinated with acetonitrile (600 µL). Quantification was carried out, acquiring two MRM transitions for each compound in positive ionization mode. Chromatographic separation was achieved with a C18 column. Limits of quantification ranged from 0.05 to 5 ng/mL. Bias and precision were always within the acceptance criteria. Ion enhancement and suppression effects were observed depending on the substance. The method validated here was applied to a real case, proving to be suitable for PM analysis. CSF and blood were positive for methadone (460 vs. 280 ng/mL), cocaine (125 vs. 69 ng/mL), benzoylecgonine (4640 vs. 3160 ng/mL), and lorazepam (19 vs. 25 ng/mL). In the future, this will be useful for the evaluation of CSF as a valuable alternative matrix in PM investigations. Full article

Managing cancer-related pain poses significant challenges, prompting research into alternative approaches such as ketamine. This systematic review aims to analyze and summarize the impact of ketamine as an adjuvant to opioid therapy for cancer-related pain. We conducted a literature review in MEDLINE, EMBASE, and Scopus from 1 January 1982 to 20 October 2023. Abstracts were screened against inclusion criteria, and eligible studies underwent a full-text review. Data was extracted from the included studies, and a framework analysis approach summarized the evidence regarding ketamine’s use in patients with cancer. A total of 21 randomized clinical trials were included, and the quality of all the included studies was good or fair. Significant improvements in pain scores and reduced morphine consumption were consistently observed with intravenous ketamine administration for postoperative pain control, particularly when combined with other analgesics such as morphine. Ketamine was less effective when used as an analgesic for chronic pain management, with several studies on neuropathic pain or chemotherapy-induced neuropathy finding minimal significant effect on reduction of pain scores or morphine requirements. The efficacy of ketamine in pain management appears to depend on factors such as dosage, route of administration, and patient population. Full article

If there is one poet who has been widely represented under a legendary light, it is Elizabeth Barrett Browning (1806–1861), mostly through the figure of a secluded invalid. Barrett Browning’s illness and death have been romanticised ever since her own time, with multiple rumours and theories mostly focusing on the fact that her illness was ‘miraculously dispelled’ by ‘love’ and only reappeared gradually to take the poet’s life. This article proposes yet another and quite different diagnosis for Barrett Browning’s illness, theorising on the possibility that Barrett Browning’s ailment was a pulmonary congenital malformation, which remained misdiagnosed due to the lack of medical technology at the time. Several of the diagnoses given to Barrett Browning by her medical practitioners, contemporary and posthumous biographers and other scholars are presented and compared, alongside my own hypothesis. In addition, Barrett Browning’s arguable morphine dependency is reassessed in order to explore its impact on her illness, with the possibility that it exacerbated or even caused some of her symptoms. This reassessment also explores the role that morphine played in Barrett Browning’s death, suggesting an accidental overdose possibly overlooked by Robert Browning. Full article

Morphine, a drug of abuse used to treat moderate-to-severe pain, elicits its actions by binding to the opioid receptors. Cocaine is an example of a recreational drug that inhibits dopamine reuptake. The molecular effects of morphine and cocaine have been described in different specific brain regions. However, the systemic outcome of these drugs on the whole organism has not been fully addressed. The aim of this study is to analyse the global effects of morphine (10 μM) and cocaine (15 μM) in the expression of proteins related to the reward pathway. Zebrafish embryos were exposed to these drugs from 5 hpf (hours post-fertilisation) to 6 dpf (days post-fertilisation). Dopamine levels were determined by ELISA, and the expression of Fos proteins, Creb, its activated form p-Creb and tyrosine hydroxylase (Th) were examined by Western blot. Both drugs decreased Th levels at 72 hpf and 6 dpf and modified the expression of Fos family members, pCreb and Creb in a time-dependent manner. Morphine and cocaine exposure differentially modified dopamine levels in 72 hpf and 6 dpf zebrafish embryos. Our results indicate that drugs of abuse modify the expression of several proteins and molecules related to the activation of the reward pathway. Full article

This study explored the potential of a series of PZM21 analogues for pain treatment. Specifically, the hydroxyphenyl ring of PZM21 was replaced with a naphthyl ring, the thienyl ring was substituted with either a phenyl ring or furan rings, and the essential dimethylamine and urea groups were retained. These compounds aimed to enhance safety and minimize the adverse effects associated with opioid drugs. The research findings suggest that compound 6a does not induce β-arrestin recruitment at low-nanomolar concentrations but exhibits significant analgesic effects in established mouse models. Compared to morphine, 6a shows advantages in alleviating respiratory depression and minimizing physical dependence. Molecular docking studies underscore the pivotal role of the D147 amino acid residue in the analgesic mechanism of 6a. Consequently, 6a is a compelling candidate for the development of safer opioid analgesics and warrants further attention. Full article

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most prevalent and dose-limiting complications in chemotherapy patients, with estimates of at least 30% of patients experiencing persistent neuropathy for months or years after treatment cessation. An emerging potential intervention for the treatment of CIPN is cannabinoid-based pharmacotherapies. We have previously demonstrated that treatment with the psychoactive CB1/CB2 cannabinoid receptor agonist Δ⁹-tetrahydrocannabinol (Δ⁹-THC) or the non-psychoactive, minor phytocannabinoid cannabidiol (CBD) can attenuate paclitaxel-induced mechanical sensitivity in a mouse model of CIPN. We then showed that the two compounds acted synergically when co-administered in the model, giving credence to the so-called entourage effect. We and others have also demonstrated that CBD can attenuate several opioid-associated behaviors. Most recently, it was reported that another minor cannabinoid, cannabigerol (CBG), attenuated cisplatin-associated mechanical sensitivity in mice. Therefore, the goals of the present set of experiments were to determine the single and combined effects of cannabigerol (CBG) and cannabidiol (CBD) in oxaliplatin-associated mechanical sensitivity, naloxone-precipitated morphine withdrawal, and acute morphine antinociception in male C57BL/6 mice. Results demonstrated that CBG reversed oxaliplatin-associated mechanical sensitivity only under select dosing conditions, and interactive effects with CBD were sub-additive or synergistic depending upon dosing conditions too. Pretreatment with a selective α2-adrenergic, CB1, or CB2 receptor selective antagonist significantly attenuated the effect of CBG. CBG and CBD decreased naloxone-precipitated jumping behavior alone and acted synergistically in combination, while CBG attenuated the acute antinociceptive effects of morphine and CBD. Taken together, CBG may have therapeutic effects like CBD as demonstrated in rodent models, and its interactive effects with opioids or other phytocannabinoids should continue to be characterized. Full article