Opioid system and PET

Four opioid receptor types have been found: μ (mu, MOP, MOR), δ (delta, DOP, DOR), κ (kappa, KOP, KOR), and NOP (ORL1). Opioid receptors are members of the G protein coupled receptor family, and like many other GPCR receptors, can exist in complexes containing other opioid receptor subtypes, or other GPCRs. Membrane trafficking of the opioid receptors is tightly regulated, and agonist-induced internalization through endosomal pathway is involved in desensitization process. Opioid receptors can exist as homomers and heteromers, which affects their functions and substrate specificity. Heteromers can also be formed between opioid- and non-opioid receptors of family A GPCRs, such as α2aAR, CB1R, D1R, NK1, and many others.

Endogenous opioid receptor ligands are mostly peptides, including β-endorphin and enkephalins (for μ and δ receptors); α-neoendorphin and dynorphin A and B (for κ receptors); and nociceptin (for NOP). Endogenous opioids are stored in large dense core vesicles inside neurons; these neurons also contain fast-acting neurotransmitters, and opioids act as modulators of the action of the primary transmitter. The intracellular processing of the opioid peptide precursor is variable in different tissues and even in different brain regions, affecting the specificity of the produced peptide. Extracellular peptidases can further modulate the endogenous ligands, even increasing the affinity to certain receptor subtype, before they finally inactivate the peptide.

Opiates are well known for their involvement in the sensation of pain (also placebo effect), but opioid system is important in several physiologic processes, including cardiovascular, gastrointestinal, renal, and hepatic function, respiration, and inflammatory responses. In the brain the opioid system plays roles in mood, reward, and appetite (Nummenmaa et al., 2018).

Antagonist-induced receptor upregulation following chronic exposure is common to many receptor systems, and is well established in opioid system. Upregulation is most prominent in μ-receptors, and less so in δ- and κ-receptors. Short-term exposure leads to opioid receptor desensitization.

PET tracers

Agonist tracers of the opioid receptors must be synthesized with very high specific activity to avoid even harmful pharmacological effects, and especially in small animal studies to keep the injected mass low enough to avoid receptor saturation.


PET tracers for μ opioid receptor include the widely used agonist [11C]carfentanil, and antagonist [18F]cyclofoxy (analogue of naltrexone), which binds to both μ and κ receptors. Only the (-) enantiomer of [18F]cyclofoxy binds to the opioid receptors.

Naloxone is a MOR antagonist that is used for the treatment of opioid overdose as a nasal spray. Its time-dependent effect on MOR occupancy has been studied with [11C]carfentanil PET (Johansson et al., 2019).


[11C]methylnaltrindole is an δOR antagonist tracer.


Several PET tracers for the κ opioid receptor have been developed, including antagonists [11C]LY2795050 and [18F]LY2459989 (Naganawa et al., 2016; Li et al., 2018), and agonist [11C]GR103545.


[11C]NOP-1A and [18F]MK-0911 are ORL1 antagonist tracers.

Non-selective tracers

Diprenorphine is an antagonist for μ, δ, and κ opioid receptors, that has been labelled with both 11C and 18F (Sadzot et al., 1991; Wester et al., 2000). For instance, [18F]FDPN has been used to study endogenous opioid system by measuring opioid receptor availability.

Buprenorphine is mixed agonist/antagonist, and it has been labelled with 11C. [18F]-FE-PEO is a non-subtype selective full agonist.

See also:


Dannals RF. Positron emission tomography radioligands for the opioid system. J Label Compd Radiopharm. 2013; 56: 187-195. doi: 10.1002/jlcr.3005.

Dean R, Bilsky EJ, Negus SS (eds.): Opiate Receptors and Antagonists - From Bench to Clinic. Springer, 2009. ISBN 978-1-59745-197-0. doi: 10.1007/978-1-59745-197-0.

Gebhart GF, Schmidt RF (eds.): Encyclopedia of Pain, 2nd ed., Springer, 2013. ISBN 978-3-642-28753-4. doi: 10.1007/978-3-642-28753-4.

Hammers A, Lingford-Hughes A. Opioid imaging. Neuroimag Clin N Am. 2006; 16: 529-552. doi: 10.1016/j.nic.2006.06.004.

Henriksen G, Willoch F. Imaging of opioid receptors in the central nervous system. Brain 2008; 131: 1171-1196. doi: 10.1093/brain/awm255.

Mayberg HS, Frost JJ. Opiate receptors. In: Frost JJ, Wagner HN Jr (eds.) Quantitative Imaging: Neuroreceptors, Neurotransmitters, and Enzymes. Raven Press, 1990. pp 81-95. ISBN 0-88167-611-X.

Pasternak GW (ed.): The Opiate Receptors, 2nd ed. Humana Press, 2011. ISBN 978-1-60761-993-2. doi: 10.1007/978-1-60761-993-2.

Spampinato SM (ed.): Opioid Receptors - Methods and Protocols. Humana Press, 2015. ISBN 978-1-4939-1708-2. doi: 10.1007/978-1-4939-1708-2.

van Waarde A, Absalom AR, Visser AKD, Dierckx RAJO. Positron emission tomography (PET) imaging of opioid receptors. In: PET and SPECT of Neurobiological Systems. Springer, 2014, pp 585-623. doi: 10.1007/978-3-642-42014-6_20.

Villemagne PSR, Dannals RF, Ravert HT, Frost JJ. PET imaging of human cardiac opioid receptors. Eur J Nucl Med. 2002; 29: 1385-1388. doi: 10.1007/s00259-002-0897-z.

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Updated at: 2019-03-15
Created at: 2017-03-19
Written by: Vesa Oikonen