morphinans and Spinal-Cord-Injuries

Traumatic spinal cord injury (SCI) is a devastating condition with few efficacious drugs. Sinomenine, a bioactive alkaloid extracted from medicinal herb, has been used as a treatment of rheumatoid diseases. This present study explored the therapeutic effects of sinomenine on locomotor dysfunction and neuropathology in SCI. Our findings revealed that sinomenine mitigated neurological deficits and enhanced neuronal preservation, paralleled with a reduction of apoptosis. Also, sinomenine significantly reduced inflammatory cytokines and oxidative stress factors. We further examined erythroid-2-related factor 2 (Nrf2) nuclear translocation, which mainly controls the coordinated expression of important antioxidant and detoxification genes. An increase in Nrf2 translocation from cytoplasm to nucleus and Nrf2-mediated transactivation was observed after sinomenine administration. Knocking down Nrf2 by siRNA could counteract sinomenine-mediated anti-oxidant stress and anti-inflammation following H

Topics: Animals; Female; Hydrogen Peroxide; Inflammation; Morphinans; NF-E2-Related Factor 2; Oxidative Stress; PC12 Cells; Rats; Rats, Sprague-Dawley; Signal Transduction; Spinal Cord Injuries; Thoracic Vertebrae

Management of chronic pain is restricted by the lack of effective tools. This study evaluated the efficacies of sinomenine combined gabapentin or ligustrazine hydrochloride in treating peripheral and central chronic neuropathic pain. The study was conducted in mice with photochemically induced sciatic nerve injury, and in rats with photochemically induced spinal cord injury. For assessing the effectiveness of combined therapy, sinomenine, gabapentin or ligustrazine hydrochloride was injected intraperitoneally (i.p.), and pain behavioral tests were performed. At sub-effective dosages, pre-administration of sinomenine (for 60 min) plus gabapentin or ligustrazine hydrochloride, generated significant anti-allodynic effects in mice or rats with peripheral or central neuropathic pain. However, these effects were abolished when gabapentin or ligustrazine hydrochloride was pre-administered, and then sinomenine was given 60 min later. The combined efficacies of sinomenine and gabapentin or ligustrazine hydrochloride, cannot be blocked or reversed by the naloxone, suggesting the underlying mechanism is not mediated by opioid receptors. Moreover, following repeated treatments, sinomenine and gabapentin combination increased the baseline mechanical threshold, while generating prolonged analgesia, without introducing notable side effects. Sinomenine can enhance the efficacy of gabapentin or ligustrazine hydrochloride in rodent models of peripheral or central neuropathic pain, without introducing tolerance or other notable side effects. Findings of current study suggest that combing sinomenine and gabapentin or ligustrazine hydrochloride could be highly beneficial in neuropathic pain therapies.

Topics: Analgesics; Animals; Disease Models, Animal; Drug Synergism; Gabapentin; Male; Mice; Mice, Inbred C57BL; Morphinans; Neuralgia; Peripheral Nerve Injuries; Pyrazines; Spinal Cord Injuries

To clarify the mechanism of inhibitory action of TRK-130 (Naltalimide), a unique µ-opioid receptor partial agonist, on the micturition reflex.. The effect of TRK-130 on isovolumetric rhythmic bladder contractions (RBCs) was examined in guinea pigs, the effect of which was clarified by co-treatment with naloxone or in spinal cord transection. The effect of TRK-130 on urodynamic parameters was also observed in guinea pigs. In addition, the effect of TRK-130 on bladder contraction induced by peripheral stimulation of the pelvic nerve was investigated in rats.. TRK-130 (0.001-0.01 mg/kg, iv) dose-dependently inhibited RBCs, which was dose-dependently antagonized by naloxone; however, the antagonism susceptibility was different from morphine (1 mg/kg, iv). The minimum effective dose (0.003 mg/kg) of TRK-130 remained similar in spinal cord-transected animals. TRK-130 (0.0025 mg/kg, iv) increased bladder capacity without changing the voiding efficiency, maximum flow rate, and intravesical pressure at the maximum flow rate, whereas oxybutynin (1 mg/kg, iv) increased the bladder capacity but affected the other parameters. TRK-130 (0.005 mg/kg, iv) did not produce significant changes on the bladder contractions induced by peripheral stimulation of the pelvic nerve, while oxybutynin (1 mg/kg, iv) significantly suppressed the bladder contractions.. These results suggest that TRK-130 enhances the bladder storage function by modulating the afferent limb of the micturition reflex through µ-opioid receptors in the spinal cord. TRK-130 could be a more effective and safer therapeutic agent with a different fashion from antimuscarinics and conventional opioids for overactive bladder.

Topics: Afferent Pathways; Analgesics, Opioid; Animals; Electric Stimulation; Guinea Pigs; Male; Mandelic Acids; Morphinans; Morphine; Muscarinic Antagonists; Muscle Contraction; Muscle, Smooth; Naloxone; Narcotic Antagonists; Peripheral Nerves; Phthalimides; Rats; Rats, Wistar; Receptors, Opioid, mu; Reflex; Spinal Cord Injuries; Urinary Bladder; Urination; Urodynamics

Sinomenine is an alkaloid originally isolated from the root of the plant Sinomenium acutum. It is used in traditional medicine in China to treat rheumatic arthritis. In the present study, we evaluated the potential antinociceptive effects of sinomenine in rodents with nociceptive, inflammatory and neuropathic pain. In normal rats and mice, systemic sinomenine produced moderate antinociceptive effect in the hot plate and tail flick tests. Sinomenine also exerted analgesic effects on mechanical and heat hypersensitivity in mice after carrageenan induced inflammation. Finally, sinomenine effectively alleviated mechanical and cold allodynia in rats and mice after injury to peripheral nerve or spinal cord. The analgesic effect of sinomenine is not associated with side effects and is not reversed by the opioid receptor antagonist naloxone. Our results showed that sinomenine has a wide spectrum analgesic effect in rodent models of nociceptive, inflammatory and neuropathic pain.

Topics: Analgesics; Animals; Behavior, Animal; Carrageenan; Female; Hyperalgesia; Inflammation; Male; Mice; Morphinans; Neuralgia; Nociception; Rats; Sciatic Nerve; Spinal Cord Injuries

The potential role of N-methyl-D-aspartate (NMDA) receptors in the pathophysiology of spinal cord injury was examined in rats by comparing the effects of the non-competitive NMDA antagonist dextrorphan and the competitive NMDA antagonist 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) on the behavioral and anatomical consequences of impact trauma to the spinal cord. Treatment with either dextrorphan or CPP, administered intrathecally 15 min after trauma, significantly improved chronic (4 weeks) behavioral recovery. Treatment with CPP, but not dextrorphan, limited the decline in serotonin below the injury zone, as shown by both immunocytochemistry and high performance liquid chromatography. Beneficial effects of CPP were dose-dependent. Dextrorphan treatment also improved behavioral outcome when the drug was administered intravenously. These studies implicate NMDA receptor-mediated excitotoxins in tissue damage following spinal cord trauma and suggest that NMDA antagonists may be of value in the treatment of acute, clinical spinal cord injury.

Topics: Amino Acids; Animals; Anticonvulsants; Binding, Competitive; Dextrorphan; Injections, Spinal; Male; Morphinans; Motor Activity; Piperazines; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Spinal Cord Injuries