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Review
. 2024 Oct 11;4(1):70.
doi: 10.1186/s44158-024-00201-2.

Opioid system and related ligands: from the past to future perspectives

Laura Rullo  1 , Camilla Morosini  1 , Antonio Lacorte  1 , Marco Cristani  1 , Flaminia Coluzzi  2   3 , Sanzio Candeletti  1 , Patrizia Romualdi  4
Affiliations
Review

Opioid system and related ligands: from the past to future perspectives

Laura Rullo et al. J Anesth Analg Crit Care. .

Abstract

Chronic pain is a pathological condition affecting about 30% of population. It represents a relevant social-health issue worldwide, and it is considered a significant source of human suffering and disability, strongly affecting patients' quality of life. Despite several pharmacological strategies to guarantee an adequate pain management have been proposed over the years, opioids still represent one of the primary choices for treating moderate-to-severe pain in both cancer and non-cancer patients. However, chronic use of opioids often leads to numerous side effects, including respiratory depression, constipation, analgesic tolerance, and opioid-induced hyperalgesia (OIH), which can strongly limit their use. Given the fundamental role of opioid system in pain relief, this review provides a general overview about the main actors (endogenous opioid peptides and receptors) involved in its modulation. Furthermore, this review explores the action and the limitations of conventional clinically used opioids and describes the efficacy and safety profile of some promising analgesic compounds. A deeper understanding of the molecular mechanisms behind both analgesic effects and adverse events could advance knowledge in this field, thus improving chronic pain treatment.

Keywords: Biased agonists; Bifunctional agonists; Chronic pain; OIH; OUD (opioid use disorder); Opioids; Tolerance.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Opioid peptide precursors. Representative peptides derived from the precursors proopiomelanocortin (a), proenkephalin (b), prodynorphin (c), and pronociceptin (d)
Fig. 2
Fig. 2
Intracellular opioid receptor signaling. Ligand activation of opioid receptors causes the dissociation of the Gαi/o protein from the Gβγ subunit, subsequently modulating downstream intracellular signaling cascades. The Gα subunit mediates the activation of K+ channels and the inhibition of adenylate cyclase, resulting in cell hyperpolarization and decreased intracellular cAMP levels. Meanwhile, the Gβγ heterodimers inhibit voltage-gated calcium channels, thereby reducing calcium influx. Sustained activation of the G protein can lead to phosphorylation of the opioid receptors by G protein-coupled receptor kinases, resulting in the recruitment of β-arrestin protein, thus facilitating receptor internalization
See this image and copyright information in PMC

References

    1. Treede RD, Rief W, Barke A, Aziz Q, Bennett MI, Benoliel R, Cohen M, Evers S, Finnerup NB, First MB, Giamberardino MA, Kaasa S, Korwisi B, Kosek E, Lavand’homme P, Nicholas M, Perrot S, Scholz J, Schug S, Smith BH, Svensson P, Vlaeyen JWS, Wang SJ (2019) Chronic pain as a symptom or a disease: the IASP Classification of Chronic Pain for the International Classification of Diseases (ICD-11). Pain 160(1):19–27. 10.1097/j.pain.0000000000001384 - PubMed
    1. Coluzzi F, Rullo L, Scerpa MS, Losapio LM, Rocco M, Billeci D, Candeletti S, Romualdi P (2022) Current and future therapeutic options in pain management: multi-mechanistic opioids involving both MOR and NOP receptor activation. CNS Drugs 36(6):617–632. 10.1007/s40263-022-00924-2 - PMC - PubMed
    1. Flores-García M, Rizzo A, Garçon-Poca MZ, Fernández-Dueñas V, Bonaventura J (2023) Converging circuits between pain and depression: the ventral tegmental area as a therapeutic hub. Front Pharmacol 14:1278023. 10.3389/fphar.2023.1278023 - PMC - PubMed
    1. Caraceni A, Hanks G, Kaasa S, Bennett MI, Brunelli C, Cherny N, Dale O, De Conno F, Fallon M, Hanna M, Haugen DF, Juhl G, King S, Klepstad P, Laugsand EA, Maltoni M, Mercadante S, Nabal M, Pigni A, Radbruch L, Reid C, Sjogren P, Stone PC, Tassinari D, Zeppetella G; European Palliative Care Research Collaborative (EPCRC); European Association for Palliative Care (EAPC) (2012) Use of opioid analgesics in the treatment of cancer pain: evidence-based recommendations from the EAPC. Lancet Oncol 13(2):e58–68. 10.1016/S1470-2045(12)70040-2 - PubMed
    1. Ambrosio F, Finco G, Mattia C, Mediati R, Paoletti F, Coluzzi F, Piacevoli Q, Savoia G, Amantea B, Aurilio C, Bonezzi C, Camaioni D, Chiefari M, Costantini A, Evangelista M, Ischia S, Mondello E, Polati E, Raffaeli W, Sabato AF, Varrassi G, Visentin M, Tufano R (2006) SIAARTI Chronic Non-Cancer Pain Study Group SIAARTI recommendations for chronic noncancer pain. Minerva Anestesiol 72(11):859–880 - PubMed

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