TREATMENT of chronic pain in patients with a history of opioid addiction is difficult since tolerance to the opioid agonist effects may require extremely large opioid doses for pain control. Furthermore, insufficient pain control may be hard to discern from craving for more opioids. Although drug-free periods, also called “drug holiday,” can reestablish sensitivity to drugs used to treat Parkin...

Morphine is an effective analgesic in clinical practice; however, its long-term administration causes tolerance, thereby limiting its use. The development of opioid tolerance and its associated hyperalgesia has been associated with interactions between opioid receptors and excitatory amino acids or cytokines. Targeted inhibition of excitatory amino acidand cytokine-mediated signaling pathways m...

Previous studies have suggested that Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) can modulate opioid tolerance and dependence via its action on learning and memory. In this study, we examined whether CaMKII could directly regulate opioid tolerance and dependence. CaMKII activity was increased after the treatment with morphine (100 mg/kg s.c. or 75 mg s.c. of morphine/pellet/mouse); t...

Recently it has been revealed that some agents that are not able to interact with opioid receptors play an important role in regulating the pharmacological actions of opioids. Especially, some of them show biphasic modulation on opioid functions, which enhance opioid analgesia, but inhibit tolerance to and substance dependence on opioids. We would like to call these agents which do not interact...

Although opioids are highly effective analgesics, they are also known to induce cellular adaptations resulting in tolerance. Experimental studies are often performed in the absence of painful tissue injury, which precludes extrapolation to the clinical situation. Here we show that rats with chronic morphine treatment do not develop signs of tolerance at peripheral mu-opioid receptors (micro-rec...

Protein phosphorylation is a key posttranslational modification mechanism controlling the conformation and activity of many proteins. Increasing evidence has implicated an essential role of phosphorylation by several major protein kinases in promoting and maintaining opioid tolerance. We review some of the most recent studies on protein kinase C (PKC), cyclic AMP dependent protein kinase A (PKA...

introduction: sex differences are observed in the development of tolerance to antinociceptive effect of opioid drugs such as morphine, but the underlying mechanisms remain unclear. critical role of glutamate in the development and maintenance of opioid tolerance has been reported by many investigators. there are also evidences about interaction between gonadal hormones and neuromodulatory syste...

The cellular basis of tolerance to, and dependence upon, many types of drugs, including opioids, has long defied identification. Tolerance to opioids cannot be explained solely on the basis of modification of opioid receptors or altered metabolism or disposition of the opioid. The development of tolerance following chronic exposure to opioids presents at least three different types of change in...

In contrast to endogenous opioids, the highly addictive drug morphine activates the mu-opioid receptor without causing its rapid endocytosis. It has recently been reported that coapplication of low concentrations of [d-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO) facilitates the ability of morphine to stimulate mu-opioid receptor endocytosis and prevents the development of morphine toleranc...

Background µ-Opioid receptor internalization is considered to be critically linked to antinociceptive tolerance. Although µ-opioid receptor agonists have been administered simultaneously with other drugs to control pain, little information is available regarding opioid–opioid interactions. Therefore, the present study was designed to further investigate the utility of a new G protein-biased lig...