Although morphine is a gold standard medication, long-term opioid use is associated with serious side effects, such as morphine-induced hyperalgesia (MIH) and anti-nociceptive tolerance. Microglia-to-neuron signalling is critically involved in pain hypersensitivity. However, molecules that control microglial cellular state under chronic morphine treatment remain unknown. Here we show that the m...

Introduction: Ultra low dose (ULD) morphine induces hyperalgesia which is mediated by excitatory Gscoupled opioid receptors. This study was designed to investigate the development of tolerance to hyperalgesic effect of morphine. Also we attempt to seek possible similarity, in view of Gs proteins, between hyperalgesic effect of ULD and hyperalgesic effect after tolerance to HD. Method: Male Wist...

It is proposed that the direct analgesic effect of morphine becomes attenuated over the course of successive administrations of the narcotic by a conditioned, compensatory, hyperalgesic response elicited by the administration procedure, the net result being analgesic tolerance. Using the "hot plate" analgesia assessment situation with rats, this conditioning view of tolerance is supported by se...

The steady-state mRNA levels of the NMDA receptor NR1 subunit were determined by a quantitative solution hybridization assay in selected CNS regions associated with antinociception in the rat. Tissues were obtained by microdissection from rats treated chronically with morphine alone or in combination with LY274614, a competitive NMDA receptor antagonist. Morphine treatment for 7 days resulted i...

BACKGROUND Direct or indirect acting cholinergic muscarinic agonists such as neostigmine, are potent antinociceptives when administered intrathecally (i.t.). This study examines whether spinal neostigmine tolerance and cross-tolerance to spinal morphine occurs. METHODS Rats (32/group) were implanted with miniosmotic pumps delivering either i.t. saline 1 microl h(-1) (S), morphine 10 nmol micr...

Neuropathic pain is a complication of inflammation, infection or some diseases such as diabetes. Opioids are used as a salvage therapy for neuropathic pain but tolerance restricts their use. In our previous study we have observed an increase of Nitric Oxide in diabetes and in morphine tolerance. This study was performed to clarify the role of inducible nitric oxide synthase, iNOS, and cationic ...

Repeated administration of morphine is associated with the development of tolerance, yet the mechanism underlying this phenomenon is still poorly understood. Recent evidence implicating glycogen synthase kinase 3 (GSK3) in opioid receptor signaling pathways has prompted us to investigate its role in morphine tolerance. Administration of 10 mg/kg morphine i.p. to Wistar rats twice daily for 8 da...

Morphine tolerance remains an intractable problem, which hinders its prolonged use in clinical practice. Endoplasmic reticulum (ER) stress has been proved to play a fundamental role in the pathogenesis of Alzheimer's disease, diabetes, atherosclerosis, cancer, etc. In this study, we provide the first direct evidence that ER stress may be a significant driver of morphine tolerance. Binding immun...

Previous experiments have shown that mice lacking a functional delta-opioid receptor (DOR-1) gene do not develop analgesic tolerance to morphine. Here we report that mice lacking a functional gene for the endogenous ligand preproenkephalin (ppENK) show a similar tolerance deficit. In addition, we found that the DOR-1 and ppENK knock-outs as well as the NMDA receptor-deficient 129S6 inbred mouse...

Morphine is one of the most potent analgesic drugs. However, the utility of morphine in the management of chronic pain is limited by its rapid development of tolerance. Morphine exerts all of its pharmacological effects via the μ-opioid receptor. In many systems, tolerance is associated with phosphorylation and desensitization of G-protein-coupled receptors (GPCRs). In case of the μ-opioid rece...