From Pharmacology to Physiology: Endocrine Functions of μ-Opioid Receptor Networks

Abstract

The steady rise in opioid users and abusers has uncovered multiple detrimental health consequences of perturbed opioid receptor signaling, thereby creating the need to better understand the biology of these systems. Among endogenous opioid networks, μ-receptors have received special attention due to their unprecedented biological complexity and broad implications in homeostatic functions. Here, we review the origin, molecular biology, and physiology of endogenous opioids with a special focus on μ-opioid receptor networks within the endocrine system. Moreover, we summarize the current evidence supporting an involvement of the latter in regulating distinct endocrine functions. Finally, we combine these insights to present an integrated perspective on μ-opioid receptor biology and provide an outlook on future studies and unresolved questions in this field.

Keywords: GPCR; evolution; hormones; opioids; oprm1; β-endorphin; μ-receptors.

Figure 1:. Chemical structure of opioids.

Alkaloids derived from Papaver Somniferum including morphine or codeine share a common carbon-scaffold and preferentially bind to μ-opioid receptors. Semi-synthetic opioids such as Fentanyl bind and activate these receptors even more potently. Endogenous opioids all share a core amino acid pentasequence coined the “opioid motif” consisting of Tyr-Gly-Gly-Phe-Met or Leu. Enkephalins are exclusively built from these 5 amino acids, whereas all other opioids peptides exhibit various additional residues. The core opioid tetrasequence with “R” indicating the respective residue (Met/Leu-XXX) is shown above.

Figure 2:. Endogenous opioid peptides are generated from precursor proteins.

Schematic illustration of the three major opioid peptide precursor proteins (conserved between mice and humans with subtle differences; the former shown above): preproenkephalin (PENK), preprodynorphin (PDYN) and preproopiomelanocortin (POMC). Major cleavage sites consisting of Lysine (K) and Arginine (R) residues are indicated. The two core opioid motifs are highlighted in green (Tyr-Gly-Gly-Phe-Met) and orange (Tyr-Gly-Gly-Phe-Leu), respectively. Post-translational processing of each precursor generates a variety of different hormones and peptides, some of which have not been named (referred to as numbers in the figure). Lower case numbers reflect different isoforms of the same peptide that vary in their length and thus, biological activity. Note that cleavage of POMC also generates non-opioid mediators such as ACTH or MSH (Adapted from [42]). ME= Met-enkephalin, OP=octapeptide, LE= Leu-enkephalin, HP=heptapeptide, αNE= alpha neoendorphin, βNE= beta neoendorphin, A_x-y= dynorphin A variants, B_x-y= dynorphin B variants, γ1-/α- MSH= gamma1/alpha melanocyte stimulating hormone, J-Peptide= joining peptide, CLIP= corticotropin-like intermediate lobe peptide; β-/γ-LPH = beta/gamma Lipotropin; β- End_x-y=beta endorphin variants

Figure 3:. The genetic complexity of μ-receptors.

Although only a single μ-receptor encoding gene exists in humans and rodents (the latter shown above), alternative splicing of the OPRM1 pre-mRNA gives rise to a plethora of receptor variants that exhibit distinct biochemical properties. All 7TM variants contain a consensus sequence built from exons 1, 2 and 3, whereas 6 TM variants replace exon 1 with exon 11. Note that the exon nomenclature does not reflect their chromosomal locus but rather their timepoint of discovery.

Figure 4:. Expression profiles of GPCR variants determine net signaling outcomes.

Simplified mathematical modelling of signaling responses arising from the combinatorial expression of different GPCR variants in a given cell or tissue.

Figure 5:. Perturbed μ-opioid receptor activity contributes to disease.

Engagement of μ-opioid receptors (sum activity) emanates from both exogenous (pharmacological), as well as endogenous sources (endogenous opioid peptides), the latter being shaped by a plethora of factors as exemplified above. Overall, biological responses prompted by μ-receptor activation occur at the expense of energetically costly (anabolic) programs such as reproduction, the immune response or bone formation. While such changes may be temporally beneficial in the face of challenging environments, their persistence (e.g. due to long-term opioid treatment) culminates in disease.