Search Results (41)

Objective: Morphine is a widely used analgesic for severe pain, but tolerance is a major challenge in long-term pain management. This study examined the potential of Daflon^® to enhance morphine’s pain-relieving effects and to reduce tolerance in a rat model with neuropathic pain induced by partial sciatic nerve transection (PSNT). Methods: Male Wistar rats were divided into five groups: (1) Sham + Saline, (2) PSNT + Saline, (3) PSNT + morphine, (4) PSNT + Daflon, and (5) PSNT + morphine + Daflon. Morphine tolerance was induced through continuous intrathecal infusion (15 µg/µL/h, i.t.) for 7 days, starting on day 7 post-PSNT, while Daflon was administered orally (50 mg/kg/day, oral) for 7 days. Pain relief was assessed using tail-flick and paw withdrawal on days 1, 4, and 7 after osmotic pump implantation. Spinal cords were collected for immunohistochemistry to analyze glial expression, and serum biomarkers (TNF-α, IL-1β, IL-6, and IL-10) were measured to evaluate neuroinflammation. Results: The results showed that oral Daflon significantly enhanced morphine’s analgesic effects, evidenced by improved pain thresholds in all behavioral tests. Moreover, Daflon reduced morphine tolerance. Mechanistically, Daflon upregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and activated heme oxygenase-1 (HO-1), reducing oxidative stress and modulating neuroinflammation through glial regulation. Combining morphine and Daflon reduces pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) and enhances anti-inflammatory IL-10 serum level, showing a synergistic effect in managing neuropathic pain with greater efficacy and lower drug dependence. Histology and immunohistochemistry evaluations further confirmed that morphine and Daflon co-treatment substantially reduced mononuclear cell infiltration, astrocyte activation (as indicated by GFAP expression), and microglial activation (as indicated by Iba-1 expression) compared to single treatment. Conclusions: Our findings suggest that dual therapy synergistically targets both oxidative stress and inflammatory pathways, leading to stronger neuroprotection and pain relief. Importantly, the combination approach may allow for lower opioid dosages, minimizing the risks of opioid-related side effects. Overall, morphine and Daflon co-administration offers a promising and safer strategy for managing neuropathic pain and preserving spinal cord integrity. Full article

Nociceptin/orphanin FQ (N/OFQ) is a neuropeptide that activates the nociceptin opioid peptide (NOP) receptor, a G protein-coupled receptor structurally similar to classical opioid receptors but with distinct pharmacological properties. Unlike μ-opioid receptor (MOR) agonists, NOP receptor agonists provide analgesia with a reduced risk of respiratory depression, tolerance, and dependence. This review synthesizes current evidence from molecular studies, animal models, and clinical trials to evaluate the therapeutic potential of the N/OFQ–NOP system in pain management and anesthesia. A literature review was conducted through a PubMed search of English language articles published between 2015 and 2025 using keywords such as “nociceptin,” “NOP receptor,” “bifunctional NOP/MOR agonists,” and “analgesia.” Primary research articles, clinical trials, and relevant reviews were selected based on their relevance to NOP pharmacology and therapeutic application. Additional references were included through citation tracking of seminal papers. Comparisons with classical opioid systems were made to highlight key pharmacological differences, and therapeutic developments involving NOP-selective and bifunctional NOP/MOR agonists were examined. In preclinical models of chronic inflammatory and neuropathic pain, NOP receptor ago-nists reduced hyperalgesia by 30–70%, while producing minimal effects in acute pain as-says. In healthy human volunteers, bifunctional NOP/MOR agonists such as cebrano-padol provided significant pain relief, achieving ≥30% reduction in pain intensity in up to 70% of subjects, with lower incidence of respiratory depression compared with morphine. Sunobinop, another NOP/MOR agent, demonstrated reduced next-day residual effects and a favorable cognitive safety profile. Clinical data also suggest that co-activation of NOP and MOR may attenuate opioid-induced hyperalgesia and tolerance. However, challenges remain, including variability in receptor signaling and limited human trial data. The N/OFQ–NOP receptor system represents a promising and potentially safer target for analgesia and perioperative care. Future efforts should focus on developing optimized NOP ligands, incorporating personalized approaches based on receptor variability, and advancing clinical trials to integrate these agents into multimodal pain management and enhanced recovery protocols. Full article

Disruption of circadian rhythms by abnormal light exposure and reduced melatonin secretion has been linked to heightened pain sensitivity and opioid tolerance. This study evaluated how environmental light manipulation and exogenous melatonin supplementation influence pain perception and morphine tolerance in a rat model of neuropathic pain induced by partial sciatic nerve transection (PSNT). Rats were exposed to constant darkness, constant light, or a 12 h/12 h light–dark cycle for one week before PSNT surgery. Behavioral assays and continuous intrathecal (i.t.) infusion of morphine, melatonin, or their combination were conducted over a 7-day period beginning immediately after PSNT. On Day 7, after discontinued drugs infusion, an acute intrathecal morphine challenge (15 µg, i.t.) was administered to assess tolerance expression. Constant light suppressed melatonin levels, exacerbated pain behaviors, and accelerated morphine tolerance. In contrast, circadian-aligned lighting preserved melatonin rhythms and mitigated these effects. Melatonin co-infusion attenuated morphine tolerance and enhanced morphine analgesia. Reduced pro-inflammatory cytokine expression and increase anti-inflammatory cytokine IL-10 level and suppressed astrocyte activation were also observed by melatonin co-infusion during morphine tolerance induction. These findings highlight the potential of melatonin and circadian regulation in improving opioid efficacy and reduced morphine tolerance in managing neuropathic pain. Full article

Neuropeptide FF (NPFF) receptor antagonists prevent morphine-mediated antinociceptive tolerance, and compounds with dual mu opioid receptor (MOR) agonist and NPFF antagonist activity produce antinociception without tolerance. Compounds synthesized showed affinities in radioligand competition binding assays in the nM and µM range at the opioid and NPFF receptors, respectively, and displayed substitution-dependent functional profiles in the [³⁵S]GTPγS functional assay. From six compounds screened in vivo for antinociception and ability to prevent NPFF-induced hyperalgesia in mouse warm water tail withdrawal tests, compound 22b produced dose-dependent MOR-mediated antinociception with an ED₅₀ value (and 95% confidence interval) of 6.88 (4.71–9.47) nmol, i.c.v., and also prevented NPFF-induced hyperalgesia. Meanwhile, 22b did not demonstrate the respiratory depression, hyperlocomotion, or impaired intestinal transit of morphine. Moreover, repeated treatment with 22b produced a 1.6-fold rightward shift in antinociceptive dose response, significantly less acute antinociceptive tolerance than morphine. Evaluated for microsomal stability in vitro and in vivo pharmacokinetic profile, 22b showed suitable microsomal stability paired in vivo with a large apparent volume of distribution and a clearance smaller than the hepatic flow in rats, suggesting no extra-hepatic metabolism. In conclusion, the present study confirms that dual-action opioid–NPFF ligands may offer therapeutic promise as analgesics with fewer liabilities of use. Full article

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

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

Background: Newborns, including preterm infants, are capable of responding to pain. Recurrent pain exposure is associated with suboptimal motor development, cognitive impairments, abnormal brain growth, and maladapted nociceptive reactions. Problem: Current agents, primarily opioids and benzodiazepines, raise major concerns due to their adverse effects, including insufficient sedation or analgesia, withdrawal, depressed respiratory effort, tolerance, and occasional paradoxical agitation. Commonly used drugs such as midazolam and morphine have been shown to induce neuroapoptosis and neurodevelopmental abnormalities in animal studies. Evaluation—Dexmedetomidine: As a specific alpha-2 adrenergic agonist, dexmedetomidine causes a significantly lower reduction in breathing effort. It has over 800 times greater affinity for alpha-2 receptors compared to alpha-1 receptors. Common side effects include bradycardia and hypotension. Prolonged use may necessitate a transition to clonidine during the weaning process. Dexmedetomidine can be administered intravenously as a bolus or infusion or intranasally. Indications include sedation and analgesia for mechanical ventilation, therapeutic hypothermia, procedural premedication, and as an adjunct to inhalational anesthesia and nerve-blocking agents. Research across varying age groups has demonstrated that dexmedetomidine shortens periods of invasive ventilation and decreases the need for other sedatives. Neonatal studies suggest that dexmedetomidine may help accelerate the achievement of full enteral feeds and can be safely administered within specific dosage ranges without causing significant adverse events that would necessitate abrupt discontinuation. Conclusions: Dexmedetomidine can be used alone or in combination with other agents. By increasing the use of dexmedetomidine, it is possible to reduce the dosage of concurrent medications, thereby minimizing the risk of complications while still achieving the desired sedation and analgesia. Full article

Long-term opioid therapies are severely limited by the development of analgesic tolerance and gastrointestinal side effects. Camelina sativa, a plant of the Brassicaceae family, modulates the activity of peroxisome proliferator-activated receptor α (PPAR-α receptor), which is involved in the regulation of pain processing and gut physiology. The aim of this study was to evaluate the efficacy of Camelina sativa defatted seed meal (DSM) supplementation on the development of analgesic tolerance and side effects after repeated treatment with morphine in naïve mice. Co-administering Camelina sativa DSM (1 g kg⁻¹ p.o.) and morphine (10 mg kg⁻¹ s.c.) increased the efficacy and duration of the opioid-induced acute analgesic effect. Camelina supplementation also delayed the onset of tolerance to the morphine analgesic effect. The same result was obtained through either simultaneously administering morphine and camelina or administering camelina 24 h before morphine injection for the entire duration of the experiment. Camelina also counteracted intestinal damage and visceral hypersensitivity caused by morphine treatment. The beneficial effects of camelina on morphine-related analgesic efficacy and gut side effects were prevented via pre-treatment with the PPAR-α antagonist GW6471, though the latter did not influence the development of morphine tolerance. In conclusion, Camelina sativa DSM could be used as a supplement to improve the therapeutic profile of morphine. Full article

Background: Morphine analgesic tolerance (MAT) limits the clinical application of morphine in the management of chronic pain. IIK7 is a melatonin type 2 (MT2) receptor agonist known to have antioxidant properties. Oxidative stress is recognized as a critical factor in MAT. This study sought to assess the impact of IIK7 on the progression of MAT and its potential to reverse pre-existing MAT. Methods: Wistar rats underwent partial sciatic nerve transection (PSNT) surgery to induce neuropathic pain (NP). Seven days post nerve transection, we implanted an intrathecal (i.t.) catheter and linked it to an osmotic pump. Rats were randomly divided into the following groups: sham-operated/vehicle, PSNT/vehicle, PSNT/IIK7 50 ng/h, PSNT/MOR 15 g/h, and PSNT/MOR 15 g + IIK7 50 ng/h. We implanted two i.t. catheters for drug administration and the evaluation of the efficacy of IIK7 in reversing pre-established MAT. We linked one to an osmotic pump for MOR or saline continuous i.t. infusion. On the 7th day, the osmotic pump was disconnected, and 50 μg of IIK7 or the vehicle was administered through the second catheter. After 3 h, 15 μg of MOR or saline was administered, and the animal behavior tests were performed. We measured the levels of mRNA for Nrf2 and HO-1, pro-inflammatory cytokines (PICs), and the microglial and astrocyte activation in the spinal cord. Results: The co-administration of IIK7 with MOR delayed MAT development in PSNT rats by restoring Nrf2 and HO-1 while also inhibiting the microglial-cell and astrocyte activation, alongside the suppression of PICs. Additionally, a single injection of high-dose 50 μg IIK7 was efficient in restoring MOR’s antinociception in MOR-tolerant rats. Conclusions: Our results indicate that the co-infusion of ultra-low-dose IIK7 can delay MAT development and a high dose can reverse pre-existing MAT. Full article

Glucagon-like peptide 1 (GLP-1) receptor agonists are frequently used to treat type 2 diabetes and obesity. Despite the development of several drugs for neuropathic pain management, their poor efficacy, tolerance, addiction potential, and side effects limit their usage. Teneligliptin, a DPP-4 inhibitor, has been shown to reduce spinal astrocyte activation and neuropathic pain caused by partial sciatic nerve transection. Additionally, we showed its capacity to improve the analgesic effects of morphine and reduce analgesic tolerance. Recent studies indicate that GLP-1 synthesized in the brain activates GLP-1 receptor signaling pathways, essential for neuroprotection and anti-inflammatory effects. Multiple in vitro and in vivo studies using preclinical models of neurodegenerative disorders have shown the anti-inflammatory properties associated with glucagon-like peptide-1 receptor (GLP-1R) activation. This study aimed to investigate the mechanism of antinociception and the effects of the GLP-1 agonist semaglutide (SEMA) on diabetic neuropathic pain in diabetic rats. Methods: Male Wistar rats, each weighing between 300 and 350 g, were categorized into four groups: one non-diabetic sham group and three diabetic groups. The diabetic group received a single intraperitoneal injection of streptozotocin (STZ) at a dosage of 60 mg/kg to induce diabetic neuropathy. After 4 weeks of STZ injection, one diabetic group was given saline (vehicle), and the other two were treated with either 1× SEMA (1.44 mg/kg, orally) or 2× SEMA (2.88 mg/kg, orally). Following a 4-week course of oral drug treatment, behavioral, biochemical, and immunohistochemical analyses were carried out. The mechanical allodynia, thermal hyperalgesia, blood glucose, advanced glycation end products (AGEs), plasma HbA1C, and spinal inflammatory markers were evaluated. Results: SEMA treatment significantly reduced both allodynia and hyperalgesia in the diabetic group. SEMA therapy had a limited impact on body weight restoration and blood glucose reduction. In diabetic rats, SEMA lowered the amounts of pro-inflammatory cytokines in the spinal cord and dorsal horn. It also lowered the activation of microglia and astrocytes in the dorsal horn. SEMA significantly reduced HbA1c and AGE levels in diabetic rats compared to the sham control group. Conclusions: These results indicate SEMA’s neuroprotective benefits against diabetic neuropathic pain, most likely by reducing inflammation and oxidative stress by inhibiting astrocyte and microglial activity. Our findings suggest that we can repurpose GLP-1 agonists as potent anti-hyperalgesic and anti-inflammatory drugs to treat neuropathic pain without serious side effects. Full article

Morphine is an important pain reliever employed in pain management, its extended utilize is hindered by the onset of analgesic tolerance and oxidative stress. Long-term morphine administration causes elevated production of reactive oxygen species (ROS), disrupting mitochondrial function and inducing oxidation. Sirtuin 3 (SIRT3), a mitochondrial protein, is essential in modulating ROS levels by regulating mitochondrial antioxidant enzymes as manganese superoxide dismutase (MnSOD). Our investigation focused on the impact of SIRT3 on hyperalgesia and morphine tolerance in mice, as evaluating the antioxidant effect of the polyphenolic fraction of bergamot (BPF). Mice were administered morphine twice daily for four consecutive days (20 mg/kg). On the fifth day, mice received an acute dose of morphine (3 mg/kg), either alone or in conjunction with BPF or Mn (III)tetrakis (4-benzoic acid) porphyrin (MnTBAP). We evaluated levels of malondialdehyde (MDA), nitration, and the activity of SIRT3, MnSOD, glutamine synthetase (GS), and glutamate 1 transporter (GLT1) in the spinal cord. Our findings demonstrate that administering repeated doses of morphine led to the development of antinociceptive tolerance in mice, accompanied by increased superoxide production, nitration, and inactivation of mitochondrial SIRT3, MnSOD, GS, and GLT1. The combined administration of morphine with either BPF or MnTBAP prevented these effects. Full article

Opioid abuse in the United States has been increasing at an alarming rate over the past 20 years. Sex differences are documented for the rates of opioid-related overdoses, abuse patterns, and drug-induced physiological effects. In our previous study, we demonstrated that chronic oxycodone administration in young female rats is associated with neurodegeneration in the brain. Males and females are susceptible to neurodegenerative diseases via differing mechanisms. To investigate whether opioid exposure affects males and females differently, we treated young mice with chronic morphine. We observed that females had stronger antinociceptive responses to acute morphine and showed a delayed development of tolerance. Males had a higher basal Bax level in the brain that correlated with a higher number of apoptotic cells. Morphine increased Bax levels in both males and females without affecting the numbers of apoptotic cells. Morphine increased activated caspase 3 in axons and increased the MBP level in plasma only in females, suggesting a demyelination process. Our data suggest that males are protected from demyelination by having a higher basal BDNF level. Altogether, our results suggest that males and females have different molecular signaling underlying their patterns in the development of morphine tolerance and drug-induced neuronal degeneration. Full article

Fibromyalgia (FM) is a chronic pain condition characterized by widespread musculoskeletal pain and other frequent symptoms such as fatigue, sleep disturbance, cognitive impairment, and mood disorder. Based on the view that intermittent stress would be the most probable etiology for FM, intermittent cold- and intermittent psychological stress-induced generalized pain (ICGP and IPGP) models in mice have been developed and validated as FM-like pain models in terms of the patho-physiological and pharmacotherapeutic features that are shared with clinical versions. Both models show long-lasting and generalized pain and female-predominant sex differences after gonadectomy. Like many other neuropathic pain models, ICGP and IPGP were abolished in lysophosphatidic acid receptor 1 (LPAR₁) knock-out mice or by LPAR₁ antagonist treatments, although deciding the clinical importance of this mechanism depends on waiting for the development of a clinically available LPAR₁ antagonist. On the other hand, the nonsteroidal anti-inflammatory drug diclofenac with morphine did not suppress hyperalgesia in these models, and this is consistent with the clinical findings. Pharmacological studies suggest that the lack of morphine analgesia is associated with opioid tolerance upon the stress-induced release of endorphins and subsequent counterbalance through anti-opioid NMDA receptor mechanisms. Regarding pharmacotherapy, hyperalgesia in both models was suppressed by pregabalin and duloxetine, which have been approved for FM treatment in clinic. Notably, repeated treatments with mirtazapine, an α2 adrenergic receptor antagonist-type antidepressant, and donepezil, a drug for treating Alzheimer’s disease, showed potent therapeutic actions in these models. However, the pharmacotherapeutic treatment should be carried out 3 months after stress, which is stated in the FM guideline, and many preclinical studies, such as those analyzing molecular and cellular mechanisms, as well as additional evidence using different animal models, are required. Thus, the ICGP and IPGP models have the potential to help discover and characterize new therapeutic medicines that might be used for the radical treatment of FM, although there are several limitations to be overcome. Full article

Morphine-induced antinociception is partially reduced in interleukin-31 (IL-31) receptor A (IL-31RA)-deficient mice, indicating that IL-31RA is crucial for morphine-induced peripheral antinociception. Herein, we examined the combined effects of IL-31 and morphine on the antinociceptive activity and itch-associated scratching behavior (LLS) in mice and elucidated the regulatory mechanisms. A hot-plate test was used to assess antinociception. LLS was automatically detected and recorded via a computer. IL-31RA mRNA expression was assessed using real-time polymerase chain reaction. Repeated pre-treatment with IL-31 resulted in significant antinociceptive activity. Repeated administration of morphine decreased the morphine-induced antinociceptive activity, LLS counts, and regular dose and inhibited IL-31-induced LLS. These results suggested that the repeated administration of morphine depleted inter-neuronal IL-31RA levels, preventing morphine-induced antinociception. Therefore, IL-31 may be helpful as an adjunct analgesic to morphine. To explore the benefits of IL-31, its influence on morphine-induced antinociceptive tolerance in mice was examined. An IL-31 and morphine combination increased the analgesic action, which increased the expression of DRG neuronal IL-31RA, elucidating the site of peripheral antinociception of morphine. This site may induce exocytosis of IL-31RA in the sensory nervous system. Collectively, the suppressive effect of IL-31 on morphine-induced antinociceptive tolerance may result from IL-31RA supplementation in sensory nerves. Full article

Peptide-based opioid ligands are important candidates for the development of novel, safer, and more effective analgesics to treat pain. To develop peptide-based safer analgesics, we synthesized a mixture-based cyclic pentapeptide library containing a total of 24,624 pentapeptides and screened the mixture-based library samples using a 55 °C warm water tail-withdrawal assay. Using this phenotypic screening approach, we deconvoluted the mixture-based samples to identify a novel cyclic peptide Tyr-[D-Lys-Dap(Ant)-Thr-Gly] (CycloAnt), which produced dose- and time-dependent antinociception with an ED₅₀ (and 95% confidence interval) of 0.70 (0.52–0.97) mg/kg i.p. mediated by the mu-opioid receptor (MOR). Additionally, higher doses (≥3 mg/kg, i.p.) of CycloAnt antagonized delta-opioid receptors (DOR) for at least 3 h. Pharmacological characterization of CycloAnt showed the cyclic peptide did not reduce breathing rate in mice at doses up to 15 times the analgesic ED₅₀ value, and produced dramatically less hyperlocomotion than the MOR agonist, morphine. While chronic administration of CycloAnt resulted in antinociceptive tolerance, it was without opioid-induced hyperalgesia and with significantly reduced signs of naloxone-precipitated withdrawal, which suggested reduced physical dependence compared to morphine. Collectively, the results suggest this dual MOR/DOR multifunctional ligand is an excellent lead for the development of peptide-based safer analgesics. Full article