Mu Opioids and Their Receptors: Evolution of a Concept

Pasternak, Gavril W.; Pan, Ying Xian

doi:10.1124/pr.112.007138

Cited by 468 publications

(550 citation statements)

References 625 publications

(726 reference statements)

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“…Despite their role in analgesia, loss of the 6TM variants were not involved with delta opioid-induced seizure activity, aversion to the kappa drug U50,488H, or α 2 -mediated hypolocomotion. These observations support the existence of parallel opioid and nonopioid pain modulatory systems and highlight the ability to dissociate unwanted delta, kappa 1 , and α 2 actions from analgesia.…”

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confidence: 54%

“…The mu opioid receptor gene, Oprm1, is complex, containing two independent promoters that generate dozens of variants through both 5′ and 3′ alternative splicing patterns that are highly conserved among multiple species (SI Appendix, Fig. S1) (1). Like the first mu opioid receptor (Oprm1) clone, MOR-1, most of the variants are traditional seven transmembrane domain (7TM) G protein-coupled receptors (GPCRs) generated from the exon 1 (E1) promoter.…”

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confidence: 99%

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Truncated mu opioid GPCR variant involvement in opioid-dependent and opioid-independent pain modulatory systems within the CNS

Marrone

Grinnell

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The clinical management of severe pain depends heavily on opioids acting through mu opioid receptors encoded by the Oprm1 gene, which undergoes extensive alternative splicing. In addition to generating a series of prototypic seven transmembrane domain (7TM) G protein-coupled receptors (GPCRs), Oprm1 also produces a set of truncated splice variants containing only six transmembrane domains (6TM) through which selected opioids such as IBNtxA (3′-iodobenzoyl-6β-naltrexamide) mediate a potent analgesia without many undesirable effects. Although morphine analgesia is independent of these 6TM mu receptor isoforms, we now show that the selective loss of the 6TM variants in a knockout model eliminates the analgesic actions of delta and kappa opioids and of α 2 -adrenergic compounds, but not cannabinoid, neurotensin, or muscarinic drugs. These observations were confirmed by using antisense paradigms. Despite their role in analgesia, loss of the 6TM variants were not involved with delta opioid-induced seizure activity, aversion to the kappa drug U50,488H, or α 2 -mediated hypolocomotion. These observations support the existence of parallel opioid and nonopioid pain modulatory systems and highlight the ability to dissociate unwanted delta, kappa 1 , and α 2 actions from analgesia.GPCR | truncation | analgesia | mu opioid receptor | morphine M odulation of pain is complex, with contributions from a variety of neurotransmitter systems. The opioid systems are particularly prominent clinically because of the availability of many potent and effective drugs, particularly those acting through mu opioid receptors. The mu opioid receptor gene, Oprm1, is complex, containing two independent promoters that generate dozens of variants through both 5′ and 3′ alternative splicing patterns that are highly conserved among multiple species (SI Appendix, Fig. S1) (1). Like the first mu opioid receptor (Oprm1) clone, MOR-1, most of the variants are traditional seven transmembrane domain (7TM) G protein-coupled receptors (GPCRs) generated from the exon 1 (E1) promoter. Each contains exons 1, 2, and 3, differing only at the intracellular C terminus due to 3′ splicing. The exon 11 (E11) promoter, located ∼30 kb upstream of exon 1, generates a set of truncated proteins lacking the first transmembrane domain because of the absence of exon 1, resulting in only six transmembrane domains (6TM).Classically, opioid mechanisms were defined pharmacologically by using selective agonists and antagonists, but genetic approaches offer a more precise approach toward assessing the pharmacological contributions of the various Oprm1 splice variants. Mice have been developed that have the selective loss of only 6TM variants (E11 KO) (2), only the exon 1-containing 7TM and 1TM variants (E1 KO) (3) or the loss of all Oprm1 variants (E1/E11 KO) (4) (SI Appendix, Fig. S1). These models provide insights into the differing pharmacology of the full-length 7TM and the truncated 6TM variants. Full-length 7TM variants are essential for morphine actions (3, 5-7). However, m...

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confidence: 54%

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confidence: 99%

Truncated mu opioid GPCR variant involvement in opioid-dependent and opioid-independent pain modulatory systems within the CNS

Marrone

Grinnell

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…In spite of opioid efficacy (Pasternak and Pan, 2013) an estimated 80% of persons worldwide do not receive adequate treatment to relieve pain (WHO, 2007). The unsuitableness of therapy is often related to legal restrictions on the availability of opioid analgesics (Weber et al, 2012), furthermore adverse effects limit the use of these drugs (Morgan, 1989).…”

Section: Discussionmentioning

confidence: 99%

Acute and subchronic antinociceptive effects of nociceptin/orphanin FQ receptor agonists infused by intrathecal route in rats

Micheli

Mannelli

Guerrini

et al. 2015

European Journal of Pharmacology

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a b s t r a c tSevere pain occurs in the context of many diseases and conditions and is a leading cause of disability. Nociceptin/orphanin FQ (N/OFQ) is the endogenous ligand of the N/OFQ peptide (NOP) receptor. This peptidergic system controls pain transmission and in particular spinally administered N/OFQ has robust antinociceptive properties.The aim of this study was to investigate the spinal antinociceptive properties of NOP peptide agonists after acute and subchronic treatment in rats. Doses unable to alter motor coordination were selected. UFP-112 (full NOP agonist) and UFP-113 (partial NOP agonist) were administered intrathecally (i.t.) by spinal catheterization. Acute injection of UFP-112 induced antinociceptive response at lower dosages (0.03-1 nmol i.t.) compared to morphine and similar to N/OFQ. UFP-113 was effective in a 0.001-1 nmol i.t. dose range. The antinociceptive effects of NOP ligands were no longer evident in rats knockout for the NOP gene, while those of morphine were maintained. The continuous spinal infusion (by osmotic pumps) of 0.1 nmol/h UFP-112 and UFP-113 showed antinociceptive action comparable to 1-3 nmol/h morphine or N/OFQ. The antinociceptive effect of morphine progressively decreased and was no longer significant after 6 days of treatment. Similar results were obtained with N/OFQ, UFP-112, and UFP-113. The acute i.t. injection of morphine in animals tolerant to N/OFQ and UFP-112 evoked analgesic effects. Neither morphine nor N/OFQ induced antinociceptive effects in morphine-and UFP-113-tolerant rats. In conclusion this study highlights the analgesic efficacy and potency of UFP-112 and UFP-113 underlining the relevance of NOP system in analgesia.

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“…The expression of μ opioid receptors is specific to cell type, localization and developmental stage (Pasternak and Pan, 2013). There are several regions in the CNS associated with high levels of μ opioid receptor mRNA, such as the periaquaeductal gray, locus coeruleus and the raphe magnus.…”

Section: Perioperative Opiatesmentioning

confidence: 99%

“…There are several regions in the CNS associated with high levels of μ opioid receptor mRNA, such as the periaquaeductal gray, locus coeruleus and the raphe magnus. Among the somatosensory regions, μ opioid receptor mRNA is abundant in the dorsal horn and dorsal root ganglia, the spinal trigeminal, ambiguus and tractus solitarii nuclei, and the thalamus (Pasternak and Pan, 2013). Hwang and colleagues have shown that epigenetic factors mediate the expression of μ opioid receptors according to developmental stage.…”

Section: Perioperative Opiatesmentioning

confidence: 99%

Epigenetics in the perioperative period

Lirk

Fiegl

Weber

et al. 2015

British J Pharmacology

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The perioperative period is characterized by profound changes in the body's homoeostatic processes. This review seeks to address whether epigenetic mechanisms may influence an individual's reaction to surgery and anaesthesia. Evidence from animal and human studies suggests that epigenetic mechanisms can explain many facets of susceptibility to acute and chronic pain, making them potential therapeutic targets. Modern pain management is still based upon opiates, and both the developmental expression of opioid receptors and opioid-induced hyperalgesia have been linked to epigenetic mechanisms. In general, opiates seem to increase global DNA methylation levels. This is in contrast to local anaesthetics, which have been ascribed a global demethylating effect. Even though no direct investigations have been carried out, the potential influence of epigenetics on the inflammatory response that follows surgery seems a promising area for research. There is a considerable body of evidence that supports the involvement of epigenetics in the complex process of wound healing. Epigenetics is an important emerging research topic in perioperative medicine, with a huge potential to positively influence patient outcome. LINKED ARTICLESThis article is part of a themed section on Epigenetics and Therapy. To view the other articles in this section visit http://dx

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Mu Opioids and Their Receptors: Evolution of a Concept

Cited by 468 publications

References 625 publications

Truncated mu opioid GPCR variant involvement in opioid-dependent and opioid-independent pain modulatory systems within the CNS

Truncated mu opioid GPCR variant involvement in opioid-dependent and opioid-independent pain modulatory systems within the CNS

Acute and subchronic antinociceptive effects of nociceptin/orphanin FQ receptor agonists infused by intrathecal route in rats

Epigenetics in the perioperative period

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