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 (ORL-1 receptor). 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, NK1R, 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, 2020, and 2022; Jern et al., 2023). Physical exercise stimulates endogenous opioid release in the brain, especially in subjects with better aerobic fitness (Saanijoki et al., 2018 and 2022). Risk-taking behaviour when faced with gains correlates with increased MOR radioligand binding (Skandali et al., 2022). Reduced brain MOR availability has been observed for example in schizophrenia (Ashok et al., 2019). In females, the estrogen state influences MOR availability in the brain (Smith et al., 2006). Seasonal photoperiodic variation affects MOR availability in brains of humans and rats (Sun et al., 2021). Many opioid drugs bind to σ-receptors.

In human heart tissue, ORs are found in myocardial cells and nerve fibres (Sobanski et al., 2014).

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 radiopharmaceuticals

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 radioligands 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.

[11C]carfentanil can be used to detect increased release of endogenous opioids in human brain (Colasanti et al., 2012; Mick et al., 2014).

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.


The κORs are the most abundant ORs in the human brain (Peckys & Landwehrmeyer, 1999), and linked to AD, pain, stress, depression, and addiction.

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 (Naganawa et al., 2014).

NOP (ORL-1 receptor)

Nociceptin/orphanin FQ peptide (NOP) receptor is an opioid receptor that may play a pathophysiologic role in obesity, anxiety, and drug abuse (Witkin et al., 2014; Ubaldi et al., 2021). [11C]NOP-1A (Kimura et al., 2011; Lohith et al., 2012) and [18F]MK-0911 (Hostetler et al., 2013) are ORL-1 receptor antagonist radioligands.

For example, [11C]NOP-1A has been used to study cocaine use disorder (Narendran et al., 2019) and alcohol use disorder (Tollefson et al., 2023).

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:


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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.

Stein C. Opioid Receptors. Annu Rev Med. 2016; 67: 433-451. doi: 10.1146/annurev-med-062613-093100.

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: 2023-09-13
Created at: 2017-03-19
Written by: Vesa Oikonen