Ultra-low-dose naloxone suppresses opioid tolerance, dependence and associated changes in mu opioid receptor–G protein coupling and Gβγ signaling

Wang, H.-Y.; Friedman, Eitan; Olmstead, Mary C.; Burns, Lindsay H.

doi:10.1016/j.neuroscience.2005.06.003

Cited by 159 publications

(156 citation statements)

References 46 publications

Supporting

Mentioning

144

Contrasting

Unclassified

Order By: Relevance

“…2,46,59 These synaptic changes include a decrease in presynaptic MOR-mediated inhibition, reduced inhibition of the miniature EPSP in substantia gelatinosa neurons, a shortened afterhy-perpolarization duration in C-fibers in the L 5 dorsal root ganglion, and increased repetitive firing of Aδ-fibers during sustained depolarization. 46,59 In this study, we demonstrate a nerve injury-induced neuroplastic alteration in MOR-G protein coupling profile in ipsilateral lumbar spinal cord tissue of SNL animals.Although we previously showed that chronic opioid administration causes a shift in MOR-G protein coupling from G i/o to G s , 74 we now show that SNL injury induces this novel MOR-G s coupling ipsilateral to the injury without changing the extent of coupling to G i/o proteins. Chronic oxycodone administration to nerve-injured rats contributed to this G s coupling, as chronic oxycodone treatment significantly enhanced the level of G s coupling compared with that seen in the ipsilateral dorsal horn of vehicle-treated SNL animals.…”

contrasting

confidence: 61%

“…The MOR-G s coupling may also contribute to the development of opioid analgesic tolerance, opioid-induced hyperalgesia, and differences in μ-opioid efficacy. 19,24,38,67,74,76 Although the ultra-low-dose NTX attenuation of injury-induced MOR-G s coupling was mild compared with the suppression of chronic opioid-induced MOR-G s coupling in intact animals, oxycodone plus ultra-low-dose NTX produced profound and significant antihypersensitivities in the L 5 /L 6 SNL model. These data suggest a common mechanism of action for certain ultra-low-dose opioid antagonist/opioid combinations in preventing analgesic tolerance and in alleviating hypersensitivities in SNL rats.…”

Section: Author Manuscript Author Manuscriptmentioning

confidence: 98%

“…11,14,26,27,31,40,67,76 Remarkably, cotreatment with ultra-low-dose naloxone, an opioid antagonist, prevents the shift in G protein coupling by the MOR as well as the analgesic tolerance and dependence induced by chronic opioid treatment. 74 Recent data have revealed that a 4-picomolar interaction between the opioid antagonists naloxone or naltrexone (NTX) and the MORinteracting scaffolding protein filamin A is responsible for the prevention of MOR's G protein coupling switch 73 rather than their direct interaction with opioid receptors that occurs at much higher doses. In both preclinical and clinical studies, ultra-low doses of NTX enhance opioid analgesia and prevent opioid dependence or withdrawal signs.…”

Section: Author Manuscript Author Manuscriptmentioning

confidence: 99%

“…We used a coimmunoprecipitation procedure described below, which is an established procedure for examining the association of GPCRs with G proteins. 13,33,43,74,75,85,86 In addition, G proteins, adenylyl cyclase, and receptors interact via scaffolding proteins such as lipid rafts and caveolae, suggesting that such protein interactions survive a coimmunoprecipitation procedure. 41 Further data show that GPCRs form stable signaling complexes with their effectors during receptor activation.…”

Section: Direct Coupling Protocolmentioning

confidence: 99%

“…73 Interestingly, the doses of NTX used in this study are 10-to 100-fold higher than the NTX doses shown to enhance analgesia and prevent tolerance in intact animals yet 100-fold to 1000-fold lower than doses used to block opioid analgesia via MORs. 25,35,50,56,74,84 Although we believe this to be the first study to assess oral delivery of an ultra-low-dose opioid antagonist in animals, a direct comparison with intrathecal NTX was possible with the study by Powell et al 56 The multitude of neuroplastic changes underlying neuropathic pain, including the extent of MOR-G s coupling now thought to be controlled by filamin A, 73 may contribute to the need for somewhat higher doses of NTX in alleviating hypersensitivities in nerve-injured animals compared with NTX doses reported to enhance opioid analgesia in intact rodents.In conclusion, the present work demonstrates that SNL injury, like chronic opioid treatment, induces G s coupling by MOR. This aberrant signaling may contribute to the excitatory neurotransmission in spinal dorsal horn after neuropathic injury as well as to the decreased efficacy of endogenous and exogenous MOR agonists in alleviating neuropathic pain.…”

mentioning

confidence: 99%

See 4 more Smart Citations

Oxycodone Plus Ultra-Low-Dose Naltrexone Attenuates Neuropathic Pain and Associated μ-Opioid Receptor–Gs Coupling

Largent-Milnes

Guo

Wang

et al. 2008

The Journal of Pain

View full text Add to dashboard Cite

Both peripheral nerve injury and chronic opioid treatment can result in hyperalgesia associated with enhanced excitatory neurotransmission at the level of the spinal cord. Chronic opioid administration leads to a shift in μ-opioid receptor (MOR)-G protein coupling from G i/o to G s that can be prevented by cotreatment with an ultra-low-dose opioid antagonist. In this study, using lumbar spinal cord tissue from rats with L 5 /L 6 spinal nerve ligation (SNL), we demonstrated that SNL injury induces MOR linkage to G s in the damaged (ipsilateral) spinal dorsal horn. This MOR-G s coupling occurred without changing G i/o coupling levels and without changing the expression of MOR or Gα proteins. Repeated administration of oxycodone alone or in combination with ultra-low-dose naltrexone (NTX) was assessed on the SNL-induced MOR-G s coupling as well as on neuropathic pain behavior. Repeated spinal oxycodone exacerbated the SNL-induced MOR-G s coupling, whereas ultra-low-dose NTX cotreatment slightly but significantly attenuated this G s coupling. Either spinal or oral administration of oxycodone plus ultra-low-dose NTX markedly enhanced the reductions in allodynia and thermal hyperalgesia produced by oxycodone alone and minimized tolerance to these effects. The MOR-G s coupling observed in response to SNL may in part contribute to the excitatory neurotransmission in spinal dorsal horn in neuropathic pain states. The antihyperalgesic and antiallodynic effects of oxycodone plus ultra-low-dose NTX (Oxytrex, Pain Therapeutics, Inc., San Mateo, CA) suggest a promising new treatment for neuropathic pain. KeywordsNeuropathic pain; G protein coupling; tolerance; opioids; hyperalgesia; allodynia; μ-opioid receptor Patients who have diseases such as cancer, arthritis, and diabetes often have development of painful neuropathies due to disease progression or medical treatment. HHS Public AccessAuthor manuscript J Pain. Author manuscript; available in PMC 2017 June 13. Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript approaches used in the clinic to treat these neuropathies include tricyclic antidepressants, dual-acting reuptake inhibitors, and anticonvulsants (eg, gabapentin) or combinations of these with nonsteroidal anti-flammatory drugs (NSAIDs) and opioids. However, these options often cause side effects such as dizziness and sedation and may not treat the various classifications of neuropathic pain states with comparable efficacy. 30,32,55,77 Treatment of neuropathic pain that is not responsive to first-line therapies is often limited to opioids, which can be effective acutely but have decreased efficacy after chronic exposure, leading to the use of higher doses to achieve the same level of pain relief and often resulting in opioidinduced mechanical and thermal hypersensitivities. 5,7,9,29,30,32,[69][70][71]79,81 For patients taking higher doses of opioids to achieve pain relief, the presence of unwanted side effects including tolerance, dependence, respiratory depression, and constipation furthe...

show abstract

contrasting

confidence: 61%

Section: Author Manuscript Author Manuscriptmentioning

confidence: 98%

Section: Author Manuscript Author Manuscriptmentioning

confidence: 99%

Section: Direct Coupling Protocolmentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Oxycodone Plus Ultra-Low-Dose Naltrexone Attenuates Neuropathic Pain and Associated μ-Opioid Receptor–Gs Coupling

Largent-Milnes

Guo

Wang

et al. 2008

The Journal of Pain

View full text Add to dashboard Cite

show abstract

Clinical Pharmacology of Addicting Drugs

Liu

Derendorf

2010

Addictive Disorders in Medical Populations

View full text Add to dashboard Cite

How to design an opioid drug that causes reduced tolerance and dependence

Berger

Whistler

2010

Annals of Neurology

View full text Add to dashboard Cite

Mu opioid receptor (MOR) agonists such as morphine are extremely effective treatments for acute pain. In the setting of chronic pain, however, their long-term utility is limited by the development of tolerance and physical dependence. Drug companies have tried to overcome these problems by simply "dialing up" signal transduction at the receptor, designing more potent and efficacious agonists and more long-lasting formulations. Neither of these strategies has proven to be successful, however, because the net amount of signal transduction, particularly over extended periods of drug use, is a product of much more than the pharmacokinetic properties of potency, efficacy, half-life, and bioavailability, the mainstays of traditional pharmaceutical screening. Both the quantity and quality of signal transduction are influenced by many regulated processes, including receptor desensitization, trafficking, and oligomerization. Importantly, the efficiency with which an agonist first stimulates signal transduction is not necessarily related to the efficiency with which it stimulates these other processes. Here we describe recent findings that suggest MOR agonists with diminished propensity to cause tolerance and dependence can be identified by screening drugs for the ability to induce MOR desensitization, endocytosis, and recycling. We also discuss preliminary evidence that heteromers of the delta opioid receptor and the MOR are pronociceptive, and that drugs that spare such heteromers may also induce reduced tolerance.Opioids have been used to treat pain for well over 5,000 years. 1 Before the 19th century, the drug of choice was opium, the resin released from the seed pods of the opium poppy. The potency of opium varied greatly from batch to batch, making it impossible to standardize dosage and greatly increasing the risk of overdose. The purification of morphine from opium in 1803 finally solved this problem and greatly improved the safety of using opioids; however, once drug doses were easily quantifiable, the problem of tolerance, defined as the need for higher doses of drug to achieve the same effect, became increasingly apparent. Tolerance was frequently accompanied by physical dependence, the need for continued drug use to prevent somatic and affective withdrawal symptoms, and in some cases by addiction.Scientists have assumed, or at least hoped, that the biological mechanisms mediating opioid analgesia are distinct from, and can be divorced from, those mediating tolerance, dependence, and addiction, and from the time of morphine's discovery, they have tried to develop opioids with a reduced propensity to cause these negative sequelae of prolonged opioid use. Two hundred years later, however, morphine is still a mainstay of modern pain management, and Many attempts to develop a better opioid have been based on flawed or incomplete hypotheses of tolerance development. As a case in point, both heroin and sustained release oxycodone (trade name OxyContin), today 2 of the most highly sought after opioid drugs of ...

show abstract

Ultra-low-dose naloxone suppresses opioid tolerance, dependence and associated changes in mu opioid receptor–G protein coupling and Gβγ signaling

Cited by 159 publications

References 46 publications

Oxycodone Plus Ultra-Low-Dose Naltrexone Attenuates Neuropathic Pain and Associated μ-Opioid Receptor–Gs Coupling

Oxycodone Plus Ultra-Low-Dose Naltrexone Attenuates Neuropathic Pain and Associated μ-Opioid Receptor–Gs Coupling

Clinical Pharmacology of Addicting Drugs

How to design an opioid drug that causes reduced tolerance and dependence

Contact Info

Product

Resources

About