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Opioid Receptor Interactions
Published by Anonymous on 2007/9/30 (2812 reads)
1: Curr Drug Targets. 2007 Jan;8(1):185-96.

Re-discussion of the importance of ionic interactions in stabilizing ligand-opioid receptor complex and in activating signal transduction.

Gentilucci L, Squassabia F, Artali R.

Dipartimento di Chimica G. Ciamician, Universitŕ degli Studi di Bologna, via Selmi 2, 40126-Bologna, Italy. luca.gentilucci@unibo.it

Among the many receptor classes of the GPCR family, ORs constitute a privileged drug target for their involvement in pain modulation and in a number of physiological functions and behavioural effects. Endogenous and exogenous opioid agonists have been the subject of intense investigations aiming to develop safe and potent analgesics for clinical practice; however, despite the large number of highly selective opioid agonists so far discovered, there is no convincing alternative to the use of morphine, fentanyls, and their derivatives. Alternative compounds could be very useful for treating pain forms "resistant" to the usual therapeutic agents. The recent discovery of a small number of atypical opioid agonists can furnish promising candidates for the development of alternative analgesic. In particular, a few molecules exist that can bind and activate ORs even deprived of the "minimal pharmacological requisites" generally considered to be necessary. In these cases it appears that receptor activation must be based on different ligand-receptor interaction mechanisms. Taken together, the data discussed in the review suggest that the prevailing assumptions about OR binding need revision. In particular, they strengthen the evidence that ORs can bind ligands via diverse binding modes, and in some cases an electrostatic interaction is not an absolute requirement.

Publication Types:
Research Support, Non-U.S. Gov't

PMID: 17266541 [PubMed - indexed for MEDLINE]


2: AAPS J. 2006 Mar 10;8(1):E118-25.

Opioid ligands with mixed mu/delta opioid receptor interactions: an emerging approach to novel analgesics.

Ananthan S.

Organic Chemistry Department, Southern Research Institute, Birmingham, AL, USA. ananthan@sri.org

Opioids are widely used in the treatment of severe pain. The clinical use of the opioids is limited by serious side effects such as respiratory depression, constipation, development of tolerance, and physical dependence and addiction liabilities. Most of the currently available opioid analgesics exert their analgesic and adverse effects primarily through the opioid mu receptors. A large number of biochemical and pharmacological studies and studies using genetically modified animals have provided convincing evidence regarding the existence of modulatory interactions between opioid mu and delta receptors. Several studies indicate that delta receptor agonists as well as delta receptor antagonists can provide beneficial modulation to the pharmacological effects of mu agonists. For example, delta agonists can enhance the analgesic potency and efficacy of mu agonists, and delta antagonists can prevent or diminish the development of tolerance and physical dependence by mu agonists. On the basis of these observations, the development of new opioid ligands possessing mixed mu agonist/delta agonist profile and mixed mu agonist/delta antagonist profile has emerged as a promising new approach to analgesic drug development. A brief overview of mu-delta interactions and recent developments in identification of ligands possessing mixed mu agonist/delta agonist and mu agonist/delta antagonist activities is provided in this report.

Publication Types:
Research Support, N.I.H., Extramural

PMID: 16584118 [PubMed - indexed for MEDLINE]


3: Alcohol Alcohol. 2005 Jan-Feb;40(1):25-34. Epub 2004 Nov 18.

Interactions between cannabinoid and opioid receptor systems in the mediation of ethanol effects.

Manzanares J, Ortiz S, Oliva JM, Pérez-Rial S, Palomo T.

Edificio Materno-Infantil, Planta 6, 613-A, Hospital Universitario 12 de Octubre, Avda. Cordoba s/n, 28041 Madrid, Spain. jmanzanares6@terra.es

Over the past few years, advances in the investigation of the neurochemical circuits involved in the development and treatment of alcohol dependence have identified peptides and receptors as potential key targets in the treatment of problems related to alcohol consumption. The endogenous opioid system is modified by alcohol intake in areas of the brain related to reward systems, and differential basal levels of opioid gene expression are found in rodents with a high preference for ethanol. This suggests a greater vulnerability to alcohol consumption in relation to differences in genetic background. Further evidence of the involvement of opioid peptides in alcohol dependence is the ability of the opioid antagonist naltrexone to reduce alcohol intake in animal models of dependence and in alcohol-dependent patients. Abundant evidence indicates that the activation of cannabinoid receptors stimulates the release of opioid peptides, therefore the cannabinoid receptor antagonists may presumably alter opioid peptide release, thus facilitating the reduction of ethanol consumption. However, little is known about the effects of ethanol on the endogenous cannabinoid system, the vulnerability of cannabinoid receptors to alcohol intake or their neurochemical implications in reducing consumption of alcohol. In this paper, we review the role of opioid and cannabinoid receptor systems, their vulnerability to alcohol intake and the development of dependence, and the targeting of these systems in the treatment of alcoholism.

Publication Types:

PMID: 15550451 [PubMed - indexed for MEDLINE]


4: Life Sci. 2003 Aug 29;73(15):1873-93.

Opioid receptor interactions: local and nonlocal, symmetric and asymmetric, physical and functional.

Smith AP, Lee NM.

California Pacific Medical Center Research Institute, 2330 Clay St., San Francisco, CA 94115, USA.

The pharmacological effects of opioid drugs and endogenous opioid peptides are mediated by several kinds of receptors, the major ones being mu, delta and kappa. Though classically it has been thought that a particular effect mediated by a drug or other ligand results from its interaction with a single type of receptor, accumulating evidence demonstrates that interactions between receptors play a major role in opioid actions. These interactions may be either local, involving receptors within the same tissue, or nonlocal, between receptors located in different tissues. Nonlocal interactions always involve intercellular mechanisms, whereas local interactions may involve either intercellular or intracellular interactions, the latter including physical association of receptors. Both local and nonlocal interactions, moreover, may be either symmetric, with ligand interaction at one receptor affecting interaction at the other, or asymmetric; and either potentiating or inhibitory. In this article we discuss major examples of these kinds of interactions, and their role in the acute and chronic effects of opioids. Knowledge of these interactions may have important implications for the design of opioids with more specific actions, and for eliminating the addictive liability of these drugs.

Publication Types:

PMID: 12899914 [PubMed - indexed for MEDLINE]


5: Neurosci Biobehav Rev. 2001 Jun;25(4):343-53.

Opioid-NMDA receptor interactions may clarify conditioned (associative) components of opioid analgesic tolerance.

Bespalov AY, Zvartau EE, Beardsley PM.

Department of Psychopharmacology, Valdman Institute of Pharmacology, Pavlov Medical University, 6/8 Lev Tolstoy Str., St Petersburg 197089, Russia. abespalov@spmu.rssi.ru

Recent evidence suggests that acute administration of opioid analgesic drugs (such as morphine or heroin) produces delayed hyperalgesia. This hyperalgesic response is likely to result from hyperactivation of NMDA receptors triggered by stimulation of opioid receptors and may mediate acute tolerance. In support of this hypothesis, blockade of NMDA receptors attenuates opioid-induced delayed hyperalgesia and prolongs the duration of antinociceptive activity of morphine. Furthermore, the NMDA receptor-induced hyperalgesia is likely an unconditioned response to opioid receptor stimulation that becomes spatiotemporally associated with environmental cues accompanying repeated opioid exposure. This hypothesis conforms to the traditional Pavlovian requirement for conditioned and unconditioned responses to be qualitatively similar. In support of the role of NMDA receptor hyperactivation in morphine tolerance, NMDA receptor antagonists have been shown to block development of analgesic tolerance induced by repeated exposures to morphine. The view of the conditioned nature of opioid tolerance may be significantly extended by assuming that upon repeated drug administration an early-onset effect of a drug may become a predictive stimulus for a later-onset effect and, consequentially, it may become empowered to elicit the later-onset effect itself. Such 'intra-drug' conditioning hypothesis is well in line with the current experimental evidence but further studies will be needed to verify it directly.

Publication Types:

PMID: 11445139 [PubMed - indexed for MEDLINE]


6: J Pain Symptom Manage. 2000 Jan;19(1 Suppl):S7-11.

NMDA-receptor antagonists and opioid receptor interactions as related to analgesia and tolerance.

Price DD, Mayer DJ, Mao J, Caruso FS.

Department of Oral and Maxillofacial Surgery, University of Florida, USA.

A model proposing that N-methyl-D-aspartate (NMDA) receptor and opioid receptor mechanisms overlap and interact within the same dorsal horn nociceptive neurons makes several predictions. First, hyperalgesia should be associated with opioid tolerance. Second, both hyperalgesia and tolerance to opioid-analgesia should be blocked by an NMDA-receptor antagonist. Results from our laboratory and others support these predictions and point to several clinical implications. One is that, in addition to preventing tolerance and dependence, combining NMDA-receptor antagonists with both opioid and nonopioid analgesics may increase their analgesic potency. Preclinical animal studies demonstrate these advantages and underscore the practicality of the combined administration of nontoxic NMDA-receptor antagonists with various types of analgesic drugs.

Publication Types:

PMID: 10687332 [PubMed - indexed for MEDLINE]

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