Analysis of opioid efficacy, tolerance, addiction and dependence from cell culture to human

Abstract

Opioid agonists are the most effective treatment for pain, but their use is limited by side effects, tolerance and fears of addiction and dependence. A major goal of opioid research is to develop agonists that have high analgesic efficacy and a low profile for side effects, tolerance, addiction and dependence. Unfortunately, there is a serious lack of experimental data comparing the degree to which different opioids produce these effects in humans. In contrast, a wide range of experimental techniques from heterologous expression systems to behaviour assessment in whole animals have been developed to study these problems. The objective of this review is to describe and evaluate these techniques as they are used to study opioid efficacy, tolerance, addiction and dependence. LINKED ARTICLESThis article is part of a themed issue on Translational Neuropharmacology. To view the other articles in this issue visit http://dx.doi.org/10. 1111/bph.2011.164.issue-4 Abbreviations CNS, central nervous system; CPP, conditioned place preference; DAMGO, D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin; ERK1/2, extracellular signal regulated kinases 1 & 2; GIRK, G-protein coupled inward rectifying potassium channel; GTPgS, guanosine 5′-3′thio-triphosphate; HEK 293, human embryonic kidney 293 cells; Kv, voltage gated potassium channel IntroductionOpioids are the most effective treatment for pain. Unfortunately, opioid use is limited by serious adverse effects such as respiratory depression, sedation and constipation. The development of tolerance, dependence and addiction during chronic opioid use further limit the clinical utility of these drugs. Opioid tolerance is characterized by a reduced responsiveness to an opioid agonist such as morphine and is usually manifest by the need to use increasing doses to achieve the desired effect. Clinically, more than 10-fold dose escalations of opioid dose in chronic pain management are common (Buntin-Mushock et al., 2005) and yet, many studies show that relatively stable doses of opioids can provide pain relief for weeks or years (Eisenberg et al., 2005;Farrar et al., 2010). Addiction as defined by the compulsive, harmful use criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition is common among recreational opioid users, but relatively rare in chronic pain patients (Cowan et al., 2001). Conservative estimates of patients prescribed longterm opioids who develop some sort of addictive disorder range from 2-6% (Fields, 2007) although both lower and higher rates have been reported (Ballantyne and LaForge, 2007;Noble et al., 2010). The terms dependence and addiction are commonly used interchangeably, but the former will be used here in the context of the withdrawal syndrome that is characteristically observed on cessation of chronic opioid use or administration of opioid antagonists and the latter to models of compulsive drug use in animals and humans. Although animal studies have reported differences in analgesic efficacy, tolerance, addiction or withdrawal for diffe...

Assessment of Morphine-induced Hyperalgesia and Analgesic Tolerance in Mice Using Thermal and Mechanical Nociceptive Modalities

“…For example, remifentanyl and fentanyl, in marked contrast with morphine, behave as full agonists and promote internalization of mu-opioid receptors 39 . Opiate analgesics such as morphine and fentanyl have half-lives in the range of hours 40 , while remifentanyl has an ultra-short half life of several minutes 41 .…”

Regulation ofµ-Opioid Receptors: Desensitization, Phosphorylation, Internalization, and Tolerance

“…Buprenorphine has lower intrinsic efficacy at MORs and thus produces less respiratory depression, making it safer than methadone for management in opioid addicts. Nevertheless, longterm use of all MOR agonists produces adverse effects that include the development of tolerance (Williams et al, 2001;von Zastrow et al, 2003;Connor et al, 2004;Waldhoer et al, 2004;Bailey and Connor, 2005;Christie, 2008;Koch and Höllt, 2008;Morgan and Christie, 2011). Differences in agonist efficacies between opioids also have important implications for tolerance: Agonists of low efficacy will occupy and engage a larger fraction of the available receptors to produce their effects than agonists with high efficacy.…”

Endomorphin-2: A Biased Agonist at the μ-Opioid Receptor

“…Agonists at the -opioid receptor (MOPr) are extremely important drugs for the management of moderate to severe pain (Corbett et al, 2006), but use of these drugs often leads to undesirable effects, including respiratory depression, constipation, and tolerance, and there is the potential for abuse (Morgan and Christie, 2011). Therefore, there is a need to develop new analgesic drugs with fewer of the unwanted effects associated with classic opioids such as morphine (Corbett et al, 2006).…”