Tolerance opiate

Many derivatives of 4-hydroxy-3-nitro-l,X-naphthyridin-2(lH)-ones (X = 5,6,7, and 8) were claimed to have been used for treating or preventing neuronal loss associated with stroke, ischemia, CNS trauma, hypoglycemia, and surgery as well as for treating neurodegenerative diseases, chronic pain, convulsion, anxiety, and opiate tolerance (96MI2). 

Increasing evidence indicates that a chronic opiate-induced upregulation of the cAMP pathway, manifested by increased concentrations of adenylyl cyclase, PKA and several phosphoprotein substrates for the protein kinase, contributes to opiate tolerance, dependence and withdrawal exhibited by locus ceruleus neurons [66]. This upregulated cAMP pathway can be viewed as a homeostatic response of the neurons to persistent opiate inhibition of the cells. In the chronic opiate-treated state, the upregulated cAMP pathway helps return neuronal firing rates to control levels, i.e. tolerance. Upon abrupt removal of the opiate via the administration of an opiate receptor antagonist, the upregulated cAMP accounts for part of the withdrawal activation of the cells. 

Welch, S.P. and Olson, K.G. Opiate tolerance-induced modulation of free intracellular calcium in synaptosomes, LifeSci., 1991, 48, 1853-1861. 

Persson, S., Post, C., Alari, L., Nyberg, F., and Terenius, L. (1989). Increased neuropeptide-converting enzyme activities in cerebrospinal fluid of opiate-tolerant rats. Neurosci. Lett. 107, 318-322. 

Whistler JL, Chuang HH, Chu P, Jan LY, von Zastrow M. Functional dissociation of mu opioid receptor signaling and endocytosis implications for the biology of opiate tolerance and addiction. Neuron 1999 23 737-746. 

Medical Use of Opiate Drugs Acute Psychological and Physiological Effects of Opiates Chronic Effects of Opiates Tolerance... 

Nitsche JE, Schuller AG, King MA, Zengh M, Pasternak GW, Pintar JE (2002) Genetic dissociation of opiate tolerance and physical dependence in delta-opioid receptor-1 and preproenkephalin knock-out mice. J Neurosci 22 10906-10913... 

Opiate tolerance is lost quickly, so there s a high risk of fatal overdose if Eddie plans to try his usual dose of heroin/methadone. 

Another agent of this general type is nalmefene (47) Despite their useful characteristics, opiates display tolerance, addiction, abuse, and some toxic side effects Antagonists combat some of these effects, most notably respiratory depression and addiction Nalmefene reputedly has significant oral activity as a narcotic antagonist The synthesis of nalmefine concludes by Wittig olefination of naltrexone (46) to nalmefene (47) This molecular transformation resulted in a significant increase in oral potency as well (141... 

Acute physiological responses to opiate administration occur rapidly and include constricted pupils, decreased pulse rate, reduced body temperature, slowed respiration rate and impaired reflexes. In addition, there is a marked slowing of the digestive system through an altering of the tonus and motility of the stomach and intestines, allowing for greater water absorption. This last effect is not subject to tolerance, and constipation is a common side effect even for chronic users. Indeed, some report that this is the worst side effect of opiate use. 

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