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Cellular neuroadaptations to chronic opioids: tolerance, withdrawal and addiction.

ABSTRACT: A large range of neuroadaptations develop in response to chronic opioid exposure and these are thought to be more or less critical for expression of the major features of opioid addiction: tolerance, withdrawal and processes that may contribute to compulsive use and relapse. This review considers these adaptations at different levels of organization in the nervous system including tolerance at the mu-opioid receptor itself, cellular tolerance and withdrawal in opioid-sensitive neurons, systems tolerance and withdrawal in opioid-sensitive nerve networks, as well as synaptic plasticity in opioid sensitive nerve networks. Receptor tolerance appears to involve enhancement of mechanisms of receptor regulation, including desensitization and internalization. Adaptations causing cellular tolerance are more complex but several important processes have been identified including upregulation of cAMP/PKA and cAMP response element-binding signalling and perhaps the mitogen activated PK cascades in opioid sensitive neurons that might not only influence tolerance and withdrawal but also synaptic plasticity during cycles of intoxication and withdrawal. The potential complexity of network, or systems adaptations that interact with opioid-sensitive neurons is great but some candidate neuropeptide systems that interact with mu-opioid sensitive neurons may play a role in tolerance and withdrawal, as might activation of glial signalling. Implication of synaptic forms of learning such as long term potentiation and long term depression in opioid addiction is still in its infancy but this ultimately has the potential to identify specific synapses that contribute to compulsive use and relapse.

SUBMITTER: Christie MJ

PROVIDER: S-EPMC2442443 | biostudies-other | 2008 May

REPOSITORIES: biostudies-other

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Project description:Study objectiveOpioid abuse and overdose constitute an ongoing health emergency. Many presume opioids have little potential for iatrogenic addiction when used as directed, particularly in short courses, as is typical of the emergency department (ED) setting. We preliminarily explore the possibility that initial exposure to opioids by EDs could be related to subsequent opioid misuse.MethodsThis cross-sectional study surveyed a convenience sample of patients reporting heroin or nonmedical opioid use at an urban, academic ED. We estimated the proportion whose initial exposure to opioids was a legitimate medical prescription and the proportion of those prescriptions that came from an ED. Secondary measurements included the proportion of patients receiving nonopioid substances before initial opioid exposure, the source of opioids between initial exposure and onset of regular nonmedical use, and time from initial prescription to opioid use disorder.ResultsOf 59 subjects, 35 (59%; 95% confidence interval [CI] 47% to 71%) reported they were first exposed to opioids by a legitimate medical prescription, and for 10 of 35 (29%; 95% CI 16% to 45%), the prescription came from an ED. Most medically exposed subjects (28/35; 80%; 95% CI 65% to 91%) reported nonopioid substance use or treatment for nonopioid substance use disorders preceding the initial opioid exposure. Emergency providers were a source of opioids between exposure and onset of regular nonmedical use in 11 of 35 cases (31%; 95% CI 18% to 48%). Thirty-one of the 35 medically exposed subjects reported the time of onset of nonmedical use; median time from exposure to onset of nonmedical use was 6 months for use to get high (N=25; interquartile range [IQR] 2 to 36), 12 months for regular use to get high (N=24; IQR 2 to 36), 18 months for use to avoid withdrawal (N=26; IQR 2 to 38), and 24 months for regular use to avoid withdrawal (N=27; IQR 2 to 48). Eleven subjects (36%; 95% CI 21% to 53%) began nonmedical use within 2 months, and 9 of 11 (82%; 95% CI 53% to 96%) reported nonopioid substance use or treatment for alcohol abuse before initial opioid exposure.ConclusionAlthough short-term opioid administration by emergency providers is unlikely to cause addiction by itself, ED opioid prescriptions may contribute to the development of addiction in some patients. There is an urgent need for further research to estimate long-term risks of short-course opioid therapy so that the risk of iatrogenic addiction can be appropriately balanced with the benefit of analgesia.

Project description:Mixed cannabinoid receptor 1 and 2 (CB1 and CB2) agonists such as ?(9)-tetrahydrocannabinol (?(9)-THC) can produce tolerance, physical withdrawal, and unwanted CB1-mediated central nervous system side effects. Whether repeated systemic administration of a CB2-preferring agonist engages CB1 receptors or produces CB1-mediated side effects is unknown.We evaluated antiallodynic efficacy, possible tolerance, and cannabimimetic side effects of repeated dosing with a CB2-preferring agonist AM1710 in a model of chemotherapy-induced neuropathy produced by paclitaxel using CB1 knockout (CB1KO), CB2 knockout (CB2KO), and wild-type (WT) mice. Comparisons were made with the prototypic classic cannabinoid ?(9)-THC. We also explored the site and possible mechanism of action of AM1710.Paclitaxel-induced mechanical and cold allodynia developed to an equivalent degree in CB1KO, CB2KO, and WT mice. Both AM1710 and ?(9)-THC suppressed established paclitaxel-induced allodynia in WT mice. In contrast to ?(9)-THC, chronic administration of AM1710 did not engage CB1 activity or produce antinociceptive tolerance, CB1-mediated cannabinoid withdrawal, hypothermia, or motor dysfunction. Antiallodynic efficacy of systemic administration of AM1710 was absent in CB2KO mice and WT mice receiving the CB2 antagonist AM630, administered either systemically or intrathecally. Intrathecal administration of AM1710 also attenuated paclitaxel-induced allodynia in WT mice, but not CB2KO mice, implicating a possible role for spinal CB2 receptors in AM1710 antiallodynic efficacy. Finally, both acute and chronic administration of AM1710 decreased messenger RNA levels of tumor necrosis factor-? and monocyte chemoattractant protein 1 in lumbar spinal cord of paclitaxel-treated WT mice.Our results highlight the potential of prolonged use of CB2 agonists for managing chemotherapy-induced allodynia with a favorable therapeutic ratio marked by sustained efficacy and absence of tolerance, physical withdrawal, or CB1-mediated side effects.

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Cellular neuroadaptations to chronic opioids: tolerance, withdrawal and addiction.

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