Neuronal voltage-gated calcium channels play a pivotal role in the conversion of electrical signals into calcium entry into nerve endings that is required for the release of neurotransmitters. They are under the control of a number of cellular signaling pathways that serve to fine tune synaptic activities, including G-protein coupled receptors (GPCRs) and the opioid system. Besides modulating channel activity via activation of second messengers, GPCRs also physically associate with calcium channels to regulate their function and expression at the plasma membrane. In this mini review, we discuss the mechanisms by which calcium channels are regulated by classical opioid and nociceptin receptors. We highlight the importance of this regulation in the control of neuronal functions and their implication in the development of disease conditions. Finally, we present recent literature concerning the use of novel μ-opioid receptor/nociceptin receptor modulators and discuss their use as potential drug candidates for the treatment of pain.

Department of Physiology and Pharmacology Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute Cumming School of Medicine University of Calgary Calgary Canada

Institute of Biology and Medical Genetics 1st Faculty of Medicine Charles University Prague Czech Republic

Institute of Organic Chemistry and Biochemistry Czech Academy of Sciences Prague Czech Republic

Zobrazit více v PubMed

Agler HL, Evans J, Tay LH, Anderson MJ, Colecraft HM, Yue DT (2005) G protein-gated inhibitory module of N-type (ca(v)2.2) ca2+ channels. Neuron 46:891–904 PubMed DOI

Altier C, Khosravani H, Evans RM, Hameed S, Peloquin JB, Vartian BA, Chen L, Beedle AM, Ferguson SS, Mezghrani A, Dubel SJ, Bourinet E, McRory JE, Zamponi GW (2006) ORL1 receptor-mediated internalization of N-type calcium channels. Nat Neurosci 9:31–40 PubMed DOI

Andrade A, Denome S, Jiang YQ, Marangoudakis S, Lipscombe D (2010) Opioid inhibition of N-type Ca2+ channels and spinal analgesia couple to alternative splicing. Nat Neurosci 13:1249–1256 PubMed DOI PMC

Bean BP (1989) Neurotransmitter inhibition of neuronal calcium currents by changes in channel voltage dependence. Nature 340:153–156 PubMed DOI

Beaudry H, Dubois D, Gendron L (2011) Activation of spinal mu- and delta-opioid receptors potently inhibits substance P release induced by peripheral noxious stimuli. J Neurosci 31:13068–13077 PubMed DOI PMC

Beck TC, Dix TA (2019) Targeting peripheral ϰ-opioid receptors for the non-addictive treatment of pain. Future Drug Discov 1:FDD17 PubMed DOI PMC

Beckett A-H, Casy AF (1954) Synthetic analgesics: stereochemical considerations. J Pharm Pharmacol 6:986–1001 PubMed DOI

Beedle AM, McRory JE, Poirot O, Doering CJ, Altier C, Barrere C, Hamid J, Nargeot J, Bourinet E, Zamponi GW (2004) Agonist-independent modulation of N-type calcium channels by ORL1 receptors. Nat Neurosci 7:118–125 PubMed DOI

Bell TJ, Thaler C, Castiglioni AJ, Helton TD, Lipscombe D (2004) Cell-specific alternative splicing increases calcium channel current density in the pain pathway. Neuron 41:127–138 PubMed DOI

Berecki G, Motin L, Adams DJ (2016) Voltage-gated R-type calcium channel inhibition via human μ-, δ-, and κ-opioid receptors is voltage-independently mediated by Gβγ protein subunits. Mol Pharmacol 89:187–196 PubMed DOI

Berridge MJ, Bootman MD, Roderick HL (2003) Calcium signalling: dynamics, homeostasis and remodelling. Nat Rev Mol Cell Biol 4:517–529 PubMed DOI

Besse D, Lombard MC, Zajac JM, Roques BP, Besson JM (1990) Pre-and postsynaptic distribution of μ, δ and κ opioid receptors in the superficial layers of the cervical dorsal horn of the rat spinal cord. Brain Res 521:15–22 PubMed DOI

Black JL (2003) The voltage-gated calcium channel gamma subunits: a review of the literature. J Bioenerg Biomembr 35:649–660 PubMed DOI

Bourinet E, Altier C, Hildebrand ME, Trang T, Salter MW, Zamponi GW (2014) Calcium-permeable ion channels in pain signaling. Physiol Rev 94:81–140 PubMed DOI

Bourinet E, Soong TW, Stea A, Snutch TP (1996) Determinants of the G protein-dependent opioid modulation of neuronal calcium channels. Proc Natl Acad Sci USA 93:1486–1491 PubMed DOI PMC

Brody DL, Patil PG, Mulle JG, Snutch TP, Yue DT (1997) Bursts of action potential waveforms relieve G-protein inhibition of recombinant P/Q-type Ca2+ channels in HEK 293 cells. J Physiol 499:637–644 PubMed DOI PMC

Bünemann M, Frank M, Lohse MJ (2003) Gi protein activation in intact cells involves subunit rearrangement rather than dissociation. Proc Natl Acad Sci USA 100:16077–16082 PubMed DOI PMC

Bunzow JR, Saez C, Mortrud M, Bouvier C, Williams JT, Low M, Grandy DK (1994) Molecular cloning and tissue distribution of a putative member of the rat opioid receptor gene family that is not a μ, δ or κ opioid receptor type. FEBS Lett 347:284–288 PubMed DOI

Buraei Z, Yang J (2010) The ß subunit of voltage-gated Ca2+ channels. Physiol Rev 90:1461–1506 PubMed DOI

Campiglio M, Flucher BE (2015) The role of auxiliary subunits for the functional diversity of voltage-gated calcium channels. J Cell Physiol 230:2019–2031 PubMed DOI PMC

Carabelli V, Carra I, Carbone E (1998) Localized secretion of ATP and opioids revealed through single Ca2+ channel modulation in bovine chromaffin cells. Neuron 20:1255–1268 PubMed DOI

Catterall WA (2011) Voltage-gated calcium channels. Cold Spring Harb Perspect Biol 3:a003947 PubMed DOI PMC

Chee MJ, Mörl K, Lindner D, Merten N, Zamponi GW, Light PE, Beck-Sickinger AG, Colmers WF (2008) The third intracellular loop stabilizes the inactive state of the neuropeptide Y1 receptor. J Biol Chem 283:33337–33346 PubMed DOI PMC

Christoph A, Eerdekens MH, Kok M, Volkers G, Freynhagen R (2017) Cebranopadol, a novel first-in-class analgesic drug candidate: first experience in patients with chronic low back pain in a randomized clinical trial. Pain 158:1813–1824 PubMed DOI PMC

Conibear AE, Asghar J, Hill R, Henderson G, Borbely E, Tekus V, Helyes Z, Palandri J, Bailey C, Starke I, von Mentzer B, Kendall D, Kelly E (2020) A novel G protein-biased agonist at the δ opioid receptor with analgesic efficacy in models of chronic pain. J Pharmacol Exp Ther 372:224–236 PubMed DOI PMC

Courteix C, Coudoré-Civiale MA, Privat AM, Pélissier T, Eschalier A, Fialip J (2004) Evidence for an exclusive antinociceptive effect of nociceptin/orphanin FQ, an endogenous ligand for the ORL1 receptor, in two animal models of neuropathic pain. Pain 110:236–245 PubMed DOI

Crowley NA, Bloodgood DW, Hardaway JA, Kendra AM, McCall JG, Al-Hasani R, McCall NM, Yu W, Schools ZL, Krashes MJ, Lowell BB, Whistler JL, Bruchas MR, Kash TL (2016) Dynorphin controls the gain of an amygdalar anxiety circuit. Cell Rep 14:2774–2783 PubMed DOI PMC

Daniels DJ, Lenard NR, Etienne CL, Law PY, Roerig SC, Portoghese PS (2005) Opioid-induced tolerance and dependence in mice is modulated by the distance between pharmacophores in a bivalent ligand series. Proc Natl Acad Sci USA 102:19208–19213 PubMed DOI PMC

Darland T, Heinricher MM, Grandy DK (1998) Orphanin FQ/nociceptin: a role in pain and analgesia, but so much more. Trends Neurosci 21:215–221 PubMed DOI

De Waard M, Liu H, Walker D, Scott VE, Gurnett CA, Campbell KP (1997) Direct binding of G-protein betagamma complex to voltage-dependent calcium channels. Nature 385:446–450 PubMed DOI

Devilliers M, Busserolles J, Lolignier S, Deval E, Pereira V, Alloui A, Christin M, Mazet B, Delmas P, Noel J, Lazdunski M, Eschalier A (2013) Activation of TREK-1 by morphine results in analgesia without adverse side effects. Nat Commun 4:2941 PubMed DOI

Diaz A, Ruiz F, Florez J, Hurle MA, Pazos A (1995) Mu-opioidreceptor regulation during opioid tolerance and supersensitivity inrat central nervous system. J Pharmacol Exp Ther 274:1545–1551 PubMed

Ding H, Kiguchi N, Yasuda D, Daga PR, Polgar WE, Lu JJ, Czoty PW, Kishioka S, Zaveri NT, Ko MC (2018) A bifunctional nociceptin and mu opioid receptor agonist is analgesic without opioid side effects in nonhuman primates. Sci Transl Med 10:eaar3483 PubMed DOI PMC

Dolphin AC (2018a) Voltage-gated calcium channel α 2δ subunits: an assessment of proposed novel roles. F1000 Res 7:1830. https://doi.org/10.12688/f1000research.16104.1

Dolphin AC (2018b) Voltage-gated calcium channels: their discovery, function and importance as drug targets. Brain Neurosci Adv 2:1–8. https://doi.org/10.1177/2398212818794805 DOI

Dunlap K, Fischbach GD (1978) Neurotransmitters decrease the calcium ocmponent of sensory neurone action potentials. Nature 276:837–839 PubMed DOI

Dunlap K, Fischbach GD (1981) Neurotransmitters decrease the calcium conductance activated by depolarization of embryonic chick sensory neurones. J Physiol 317:519–535 PubMed DOI PMC

Evans CJ, Keith DE, Morrison H, Magendzo K, Edwards RH (1992) Cloning of a delta opioid receptor by functional expression. Science 258:1952–1955 PubMed DOI

Evans RM, You H, Hameed S, Altier C, Mezghrani A, Bourinet E, Zamponi GW (2010) Heterodimerization of ORL1 and opioid receptors and its consequences for N-type calcium channel regulation. J Biol Chem 285:1032–1040 PubMed DOI

Field MJ, Carnell AJ, Gonzalez MI, McCleary S, Oles RJ, Smith R, Hughes J, Singh L (1999) Enadoline, a selective kappa-opioid receptor agonist shows potent antihyperalgesic and antiallodynic actions in a rat model of surgical pain. Pain 80:383–389 PubMed DOI

Fujita W, Gomes I, Devi LA (2014) Revolution in GPCR signalling: opioid receptor heteromers as novel therapeutic targets: IUPHAR review 10. Br J Pharmacol 171:4155–4176 PubMed DOI PMC

Gandini MA, Souza IA, Raval D, Xu J, Pan YX, Zamponi GW (2019) Differential regulation of Cav2.2 channel exon 37 variants by alternatively spliced μ-opioid receptors. Mol Brain 12:98 PubMed DOI PMC

Gear RW, Gordon NC, Heller PH, Paul S, Miaskowski C, Levine JD (1996) Gender difference in analgesic response to the kappa-opioid pentazocine. Neurosci Lett 205:207–209 PubMed DOI

Goodchild CS, Nadeson R, Cohen, E (2004) Supraspinal and spinal cord opioid receptors are responsible for antinociception following intrathecal morphine injections. Eur J Anaesthesiol 21(3):179–185 PubMed DOI

Hawkins KN, Knapp RJ, Gehlert DR, Lui GK, Yamamura MS, Roeske LC, Hruby VJ, Yamamura HI (1988) Quantitative autoradiography of [3H] CTOP binding to mu opioid receptors in rat brain. Life Sci 42:2541–2551 PubMed DOI

Heinke B, Gingl E, Sandkühler J (2011) Multiple targets of μ-opioid receptor-mediated presynaptic inhibition at primary afferent Aδ- and C-fibers. J Neurosci 31:1313–1322 PubMed DOI PMC

Herlitze S, Garcia DE, Mackie K, Hille B, Scheuer T, Catterall WA (1996) Modulation of Ca2+ channels by G-protein beta gamma subunits. Nature 380:258–262 PubMed DOI

Herlitze S, Hockerman GH, Scheuer T, Catterall WA (1997) Molecular determinants of inactivation and G protein modulation in the intracellular loop connecting domains I and II of the calcium channel alpha1A subunit. Proc Natl Acad Sci USA 94:1512–1516 PubMed DOI PMC

Hümmer A, Delzeith O, Gomez SR, Moreno RL, Mark MD, Herlitze S (2003) Competitive and synergistic interactions of G protein beta(2) and Ca(2+) channel beta(1b) subunits with Ca(v)2.1 channels, revealed by mammalian two-hybrid and fluorescence resonance energy transfer measurements. J Biol Chem 278:49386–49400 PubMed DOI

Ikeda K, Kobayashi T, Kumanishi T, Yano R, Sora I, Niki H (2002) Molecular mechanisms of analgesia induced by opioids and ethanol: is the GIRK channel one of the keys. Neurosci Res 44:121–131 PubMed DOI

Ikeda SR (1991) Double-pulse calcium channel current facilitation in adult rat sympathetic neurones. J Physiol 439:181–214 PubMed DOI PMC

Jiang YQ, Andrade A, Lipscombe D (2013) Spinal morphine but not ziconotide or gabapentin analgesia is affected by alternative splicing of voltage-gated calcium channel CaV2.2 pre-mRNA. Mol Pain 9:67 PubMed PMC

Jones LP, Patil PG, Snutch TP, Yue DT (1997) G-protein modulation of N-type calcium channel gating current in human embryonic kidney cells (HEK 293). J Physiol 498:601–610 PubMed DOI PMC

Kang MG, Campbell KP (2003) Gamma subunit of voltage-activated calcium channels. J Biol Chem 278:21315–21318 PubMed DOI

Kieffer BL (1995) Recent advances in molecular recognition and signal transduction of active peptides: receptors for opioid peptides. Cell Mol Neurobiol 15:615–635 PubMed DOI

Kieffer BL, Befort K, Gaveriaux-Ruff C, HiRTH CHRISTIANG (1992) The delta-opioid receptor: isolation of a cDNA by expression cloning and pharmacological characterization. Proc Natl Acad Sci 89:12048–12052 PubMed DOI PMC

King MA, Rossi GC, Chang AH, Williams L, Pasternak GW (1997) Spinal analgesic activity of orphanin FQ/nociceptin and its fragments. Neurosci Lett 223:113–116 PubMed DOI

Kitchen I, Slowe SJ, Matthes HWD, Kieffer B (1997) Quantitative autoradiographic mapping of μ-, δ-and κ-opioid receptors in knockout mice lacking the μ-opioid receptor gene. Brain Res 778:73–88 PubMed DOI

Koch ED, Kapanadze S, Eerdekens MH, Kralidis G, Létal J, Sabatschus I, Ahmedzai SH (2019) Cebranopadol, a novel first-in-class analgesic drug candidate: first experience with cancer-related pain for up to 26 weeks. J Pain Symptom Manage 58:390–399 PubMed DOI

Kondo I, Marvizon JC, Song B, Salgado F, Codeluppi S, Hua XY, Yaksh TL (2005) Inhibition by spinal mu- and delta-opioid agonists of afferent-evoked substance P release. J Neurosci 25:3651–3660 PubMed DOI PMC

Kuo CC, Bean BP (1993) G-protein modulation of ion permeation through N-type calcium channels. Nature 365:258–262 PubMed DOI

Lenard NR, Daniels DJ, Portoghese PS, Roerig SC (2007) Absence of conditioned place preference or reinstatement with bivalent ligands containing mu-opioid receptor agonist and delta-opioid receptor antagonist pharmacophores. Eur J Pharmacol 566:75–82 PubMed DOI

Lin AP, Ko MC (2013) The therapeutic potential of nociceptin/orphanin FQ receptor agonists as analgesics without abuse liability. ACS Chem Neurosci 4:214–224 PubMed DOI

Linz K, Christoph T, Tzschentke TM, Koch T, Schiene K, Gautrois M, Schröder W, Kögel BY, Beier H, Englberger W, Schunk S, De Vry J, Jahnel U, Frosch S (2014) Cebranopadol: a novel potent analgesic nociceptin/orphanin FQ peptide and opioid receptor agonist. J Pharmacol Exp Ther 349:535–548 PubMed DOI

Lord JAH, Waterfield AA, Hughes J, Kosterlitz HW (1977) Endogenous opioid peptides: multiple agonists and receptors. Nature 267:495–499 PubMed DOI

Majumdar S, Grinnell S, Le Rouzic V, Burgman M, Polikar L, Ansonoff M, Pintar J, Pan YX, Pasternak GW (2011) Truncated G protein-coupled mu opioid receptor MOR-1 splice variants are targets for highly potent opioid analgesics lacking side effects. Proc Natl Acad Sci USA 108:19778–19783 PubMed DOI PMC

Mansour A, Khachaturian H, Lewis ME, Akil HUDA, Watson SJ (1987) Autoradiographic differentiation of mu, delta, and kappa opioid receptors in the rat forebrain and midbrain. J Neurosci 7:2445–2464 PubMed PMC

Marker CL, Luján R, Loh HH, Wickman K (2005) Spinal G-protein-gated potassium channels contribute in a dose-dependent manner to the analgesic effect of mu- and delta- but not kappa-opioids. J Neurosci 25:3551–3559 PubMed DOI PMC

Marker CL, Stoffel M, Wickman K (2004) Spinal G-protein-gated K+ channels formed by GIRK1 and GIRK2 subunits modulate thermal nociception and contribute to morphine analgesia. J Neurosci 24:2806–2812 PubMed DOI PMC

Melliti K, Grabner M, Seabrook GR (2003) The familial hemiplegic migraine mutation R192Q reduces G-protein-mediated inhibition of P/Q-type (Ca(V)2.1) calcium channels expressed in human embryonic kidney cells. J Physiol 546:337–347 PubMed DOI

Meunier J-C, Mollereau C, Toll L, Suaudeau C, Moisand C, Alvinerie P, Butour J-L, Guillemot J-C, Ferrara P, Monsarrat B (1995) Isolation and structure of the endogenous agonist of opioid receptor-like ORL 1 receptor. Nature 377:532–535 PubMed DOI

Mollereau C, Parmentier M, Mailleux P, Butour J-L, Moisand C, Chalon P, Caput D, Vassart G, Meunier J-C (1994) ORL1, a novel member of the opioid receptor family: cloning, functional expression and localization. FEBS Lett 341:33–38 PubMed DOI

Morikawa H, Mima H, Uga H, Shoda T, Fukuda K (1999) Opioid potentiation of N-type Ca2+ channel currents via pertussis-toxin-sensitive G proteins in NG108-15 cells. Pflugers Arch 438:423–426 PubMed

Neal CR Jr, Mansour A, Reinscheid R, Nothacker H, Civelli O, Akil H, Watson SJ Jr (1999) Opioid receptor-like (ORL1) receptor distribution in the rat central nervous system: comparison of ORL1 receptor mRNA expression with 125I-[14Tyr]-orphanin FQ binding. J Comp Neurol 412:563–605 PubMed DOI

Nozaki C, Le Bourdonnec B, Reiss D, Windh RT, Little PJ, Dolle RE, Kieffer BL, Gavériaux-Ruff C (2012) δ-Opioid mechanisms for ADL5747 and ADL5859 effects in mice: analgesia, locomotion, and receptor internalization. J Pharmacol Exp Ther 342:799–807 PubMed DOI PMC

Pan YX, Bolan E, Pasternak GW (2002) Dimerization of morphine and orphanin FQ/nociceptin receptors: generation of a novel opioid receptor subtype. Biochem Biophys Res Commun 297:659–663 PubMed DOI

Patil PG, de Leon M, Reed RR, Dubel S, Snutch TP, Yue DT (1996) Elementary events underlying voltage-dependent G-protein inhibition of N-type calcium channels. Biophys J 71:2509–2521 PubMed DOI PMC

Peciña M, Karp JF, Mathew S, Todtenkopf MS, Ehrich EW, Zubieta JK (2019) Endogenous opioid system dysregulation in depression: implications for new therapeutic approaches. Mol Psychiatry 24:576–587 PubMed DOI

Portoghese PS (1965) A new concept on the mode of interaction of narcotic analgesics with receptors. J Med Chem 8:609–616 PubMed DOI

Raingo J, Castiglioni AJ, Lipscombe D (2007) Alternative splicing controls G protein-dependent inhibition of N-type calcium channels in nociceptors. Nat Neurosci 10:285–292 PubMed DOI PMC

Sandoz G, Lopez-Gonzalez I, Grunwald D, Bichet D, Altafaj X, Weiss N, Ronjat M, Dupuis A, De Waard M (2004) Cavbeta-subunit displacement is a key step to induce the reluctant state of P/Q calcium channels by direct G protein regulation. Proc Natl Acad Sci USA 101:6267–6272 PubMed DOI PMC

Schmid CL, Kennedy NM, Ross NC, Lovell KM, Yue Z, Morgenweck J, Cameron MD, Bannister TD, Bohn LM (2017) Bias factor and therapeutic window correlate to predict safer opioid analgesics. Cell 171:1165–1175.e13 PubMed DOI PMC

Schroeder JE, Fischbach PS, Zheng D, McCleskey EW (1991) Activation of mu opioid receptors inhibits transient high- and low-threshold Ca2+ currents, but spares a sustained current. Neuron 6:13–20 PubMed DOI

Simms BA, Zamponi GW (2014) Neuronal voltage-gated calcium channels: structure, function, and dysfunction. Neuron 82:24–45 PubMed DOI

Toth PT, Shekter LR, Ma GH, Philipson LH, Miller RJ (1996) Selective G-protein regulation of neuronal calcium channels. J Neurosci 16:4617–4624 PubMed DOI PMC

Tsunoo A, Yoshii M, Narahashi T (1986) Block of calcium channels by enkephalin and somatostatin in neuroblastoma-glioma hybrid NG108-15 cells. Proc Natl Acad Sci USA 83:9832–9836 PubMed DOI PMC

Weiss N, Sandoval A, Felix R, Van den Maagdenberg A, De Waard M (2008) The S218L familial hemiplegic migraine mutation promotes deinhibition of Ca(v)2.1 calcium channels during direct G-protein regulation. Pflugers Arch 457:315–326 PubMed DOI PMC

Weiss N, Tadmouri A, Mikati M, Ronjat M, De Waard M (2007) Importance of voltage-dependent inactivation in N-type calcium channel regulation by G-proteins. Pflugers Arch 454:115–129 PubMed DOI

Wettschureck N, Offermanns S (2005) Mammalian G proteins and their cell type specific functions. Physiol Rev 85:1159–1204 PubMed DOI

Wu J, Yan Z, Li Z, Qian X, Lu S, Dong M, Zhou Q, Yan N (2016) Structure of the voltage-gated calcium channel Ca(v)1.1 at 3.6 Å resolution. Nature 537:191–196 PubMed DOI

Wu J, Yan Z, Li Z, Yan C, Lu S, Dong M, Yan N (2015) Structure of the voltage-gated calcium channel Cav11 complex. Science 350:aad2395 PubMed DOI

Zamponi GW, Bourinet E, Nelson D, Nargeot J, Snutch TP (1997) Crosstalk between G proteins and protein kinase C mediated by the calcium channel alpha1 subunit. Nature 385:442–446 PubMed DOI

Zamponi GW, Striessnig J, Koschak A, Dolphin AC (2015) The physiology, pathology, and pharmacology of voltage-gated calcium channels and their future therapeutic potential. Pharmacol Rev 67:821–870 PubMed DOI PMC

Zhao Y, Huang G, Wu Q, Wu K, Li R, Lei J, Pan X, Yan N (2019) Cryo-EM structures of apo and antagonist-bound human Ca PubMed DOI

The T-type calcium channelosome