Endogenous Opioids and Stem Cells: Comparison
Please note this is a comparison between Version 2 by Catherine Yang and Version 1 by Silvia Canaider.

Opioids are considered the oldest drugs known by humans and have been used for sedation and pain relief for several centuries. Nowadays, endogenous opioid peptides are divided into four families: enkephalins, dynorphins, endorphins, and nociceptin/orphanin FQ. They exert their action through the opioid receptors (ORs), transmembrane proteins belonging to the su-per-family of G-protein-coupled receptors, and are expressed throughout the body; the receptors are the δ opioid receptor (DOR), μ opioid receptor (MOR), κ opioid receptor (KOR), and nociceptin/orphanin FQ receptor (NOP). Endogenous opioids are mainly studied in the central nervous system (CNS), but their role has been investigated in other organs, both in physiological and in pathological conditions. Here, it is presented a revision of their role in stem cell (SC) biology, since these cells are a subject of great scientific interest due to their peculiar features and their involvement in cell-based therapies in regenerative medicine. In particular, it will be focused on the endogenous opioids’ ability to modulate SC proliferation, stress response (to oxidative stress, starvation, or damage following ischemia–reperfusion), and differentiation towards different lineages, such as neuro-genesis, vasculogenesis, and cardiogenesis.

  • endogenous opioid peptides
  • opioid receptors
  • stem cells
  • differentiation
  • stress response
  • proliferation

1. Introduction

Opioids are considered the oldest drugs known by humans and have been used for pain relief and sedation for several centuries. They are a class of compounds related in structure to the natural plant alkaloids which are extracted from the resin of the poppy plant (Papaver somniferum). Among them, morphine is the most common, active compound, which exerts its action in the central and peripheral nervous systems (CNS and PNS, respectively) through binding to the opioid receptors (ORs).

Opioids are considered the oldest drugs known by humans and have been used for pain relief and sedation for several centuries. They are a class of compounds related in structure to the natural plant alkaloids which are extracted from the resin of the poppy plant (Papaver somniferum) [1]. Among them, morphine is the most common, active compound, which exerts its action in the central and peripheral nervous systems (CNS and PNS, respectively) through binding to the opioid receptors (ORs) [2].

Nowadays, endogenous opioid peptides are divided into four families: enkephalins, dynorphins, endorphins, and nociceptin/orphanin FQ . From a molecular point of view, each opioid peptide is synthesized as a prepro and a proform, creating functional peptides after precursor processing. All peptides share a common aminoterminal sequence, Tyr-Gly-Gly-Phe-(Met/Leu), namely, the opioid motif. For this reason, the same precursor may result in different opioid peptides (Figure 1).

Nowadays, endogenous opioid peptides are divided into four families: enkephalins, dynorphins, endorphins, and nociceptin/orphanin FQ [3]. From a molecular point of view, each opioid peptide is synthesized as a prepro and a proform, creating functional peptides after precursor processing. All peptides share a common aminoterminal sequence, Tyr-Gly-Gly-Phe-(Met/Leu), namely, the opioid motif. For this reason, the same precursor may result in different opioid peptides (Figure 1) [4][5].

Figure 1. Schematic representation of human endogenous opioid families and their main functional peptides after precursor processing. For each family of peptides, the following information is reported: (i) the names of the genes (PENK, PDYN, POMC, and PNOC); (ii) the amino acid sequence of the preforms (NCBI Reference Sequence is reported in brackets next to the proform names); (iii) on the right, the names of the main functional peptides highlighted with a corresponding colour in the preform peptide sequence and in the isolated peptide sequence when it is required.

Endogenous opioid peptides (and exogenous opioids) exert their action through the opioid receptors. ORs are transmembrane proteins belonging to the super-family of G-protein-coupled receptors (GPCRs), which are widely studied due to their key role in mood disorders, drug abuse/addiction, and pain management [6][7][8]. They are expressed not only in the CNS but also in many other districts. There are four subtypes of OR: δ opioid receptor (DOR), μ opioid receptor (MOR), κ opioid receptor (KOR), and nociception/orphanin FQ (NOP) receptor.

Here it will be presented the effect od endogenous opioids on stem cells. Among all the cell types forming the body’s tissues, stem cells (SCs) are the subject of great scientific interest due to their peculiar features. In fact, they are characterized by two important properties: the ability to self-renew and the ability to differentiate into different cell types. Although the mechanisms orchestrating the biology of SCs are not completely understood, it is suggested that their fate strongly depends on the interactions with their microenvironment, called the niche. Increasing evidence states that the niche, consisting of other non-SCs, the extracellular matrix, and signaling factors, in combination with the intrinsic characteristics of SCs, consistently defines their properties and potential. Within this frame, SCs represent a particularly attractive tool for therapeutic applications and regenerative medicine.

2. Endogenous Opioids Modulate Stem Cell Proliferation and Cell Stress Response

The opportunity to modulate SC proliferation and stress response represents one of the main goals of biological SC research aimed at improving the efficiency of SC transplantation. The following Table shows the major outcomes of studies committed to evaluating the role of endogenous opioid peptides on these SC features (table complete of all references is published in [1]Table 1)

 
Table 1.
Effects of endogenous opioids on stem cell proliferation and stress response.
Opioids/Agonists Pre-Treatment Antagonists Opioid Receptor Cell Type Biological Effects Ref.
Met-enkephalin

Morphine

(10−6  M)
  Naloxone

(3 × 10−6  M)
DOR

MOR
NPCs

(from EGL of postnatal

5- and 6-day-old mice)
Morphine significantly reduced DNA content; this

effect was attenuated by naloxone co-administration.

Met-enkephalin did not alter DNA synthesis.

Opioids did not affect cell viability.
[9]
Met-enkephalin

(10−6  or 10−5  M)
    MOR hCB-CD34+  and

hPB-CD34+  cells
hCB-CD34+  expressed MOR more than hPB-CD34+  cells.

In treated hCB-CD34+  cells, phospho-MAPK was increased

by 4.7- to 6.1-fold compared to the untreated cells;

the increase of phospho-p38 was moderate.

In hCB-CD34+, met-enkephalin did not reducethe apoptosis induced by irradiation.
[10]
Dynorphin-A[1–17]

Dynorphin-A[2–17]

U50,488

(10−14  to 10−8  M)
  Nor-BNI

(10−6  M)
KOR NPCs

(from 7- to 9-week-old human fetal brain tissue)
Dynorphin-A[1–17] and U50,488 stimulated cell proliferation

and migration in a dose-dependent manner.
[11]
Morphine     MOR NSCs Theoretical hypothesis: since morphine reduces

testosterone levels, increases DHT levels, andover-expresses  p53  gene, it might prevent NSC proliferation.
[12]
Morphine sulfate

(10−6  to 1.3 × 10−5  M)
  Naloxone MOR NPCs

(from 14-day-oldmouse embryos)
Morphine decreased proliferation of NPCs and induced the caspase-3 activity in a dose-dependent manner.

Morphine induced neuronal differentiation of NPCs.
[13]
Nociceptin     NOP Mouse SSCs and

spermatocytes
Nociceptin is an upstream Sertoli cell transcription factor

that regulates SSC self-renewal

and spermatocyte meiosis.
[14]
Morphine

(10−4  M)
  Naloxone

(5 × 10−5  M)
MOR Rat NSCs Morphine decreased NSC growth

and increased apoptosis.

Morphine reduced the secretion

of insulin and insulin-like growth factors

and downregulated insulin receptor expression.
[15]
DADLE

(10−7  M)
Serum

deprivation
Naltrindole DOR hUCB-MSCs DADLE increased anti-apoptotic Bcl-2, decreased

pro-apoptotic Bax/Bad, decreased the activated caspase-3, upregulated PI3K subunit p110γ,

and activated Akt.

DADLE upregulated the release of anti-inflammatory cytokines (IL-4, IL-10, and TGF-β) and downregulated the secretion of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1).
[16]
DADLE

(10−7  M)
H2O2

(6 × 10−4  M)
  DOR hUCB-MSCs DADLE increased cell viability,

upregulated the anti-apoptotic protein Bcl-2,and suppressed the pro-apoptotic proteins Bax/Bad.

DADLE reduced intracellular ROS levels and AP sites.

DADLE downregulated UPR genes:  IRE-1α,  BiP,

PERK,  ATF-4, and  CHOP.
[17]
DADLE

(10−7  M)
H/R induced by CoCl2

(7.5 × 10−4  M)
Naltrindole DOR hUCB-MSCs DADLE increased cell viability and

reduced intracellular ROS levels.

DADLE suppressed mitochondrial complex 1 activity.

DADLE upregulated the anti-apoptotic gene  Bcl-2

while downregulating the pro-apoptotic gene  Bax  and

UPR genes  PERK,  IRE-1α,  BiP,  PERK, and  ATF-6.

DADLE upregulated the release of anti-inflammatory cytokines (IL-4, IL-10, and TGF-β) and downregulated the secretion of pro-inflammatory cytokines (TNF-α, IL-6, IFN-γ, and IL-1β).
[18]
DOR, δ opioid receptor; MOR, μ opioid receptor; NPCs, neural precursor cells; EGL, external granular layer; hCB- and hPB-CD34+ cells, human CD34+ hematopoietic stem cells obtained from umbilical cord and peripheral blood, respectively; phospho-MAPK, phosphorylated form of mitogen-activated protein kinase; phospho-p38, phosphorylated form of p38 mitogen-activated protein kinase; U50,488, trans-3,4-dichloro-N-methyl-N[2-(1-pyrolidinyl)cyclohexyl] benzeneacetamide methanesulfonate; Nor-BNI, nor-binaltorphimine; KOR, κ opioid receptor; NSCs, neural stem cells; DHT, dihydrotestosterone; p53, tumor protein p53; NOP, nociceptin/orphanin FQ receptor; SSCs, spermatogonial stem cells; DADLE, [D-Ala2, D-Leu5]-enkephalin; hUCB-MSCs, human umbilical cord blood-derived mesenchymal stem cells; Bcl-2, B-cell lymphoma 2; Bax, Bcl-2-associated X protein; Bad, Bcl-2-associated death promoter; PI3K, phosphoinositide 3-kinase; Akt, protein kinase B; H2O2, hydrogen peroxide; ROS, reactive oxygen species; AP sites, apurinic/apyrimidinic sites; UPR, unfolded protein response; IRE-1α, inositol-requiring enzyme 1 alpha; Bip, binding immunoglobulin protein; PERK, protein kinase R-like endoplasmic reticulum kinase; ATF-4, activating transcription factor 4; CHOP, C/EBP homologous protein; H/R, hypoxia/reperfusion; CoCl2, cobalt chloride; ATF-6, activating transcription factor 6; IL-4, interleukin 4; IL-10, interleukin 10; TGF-β, transforming growth factor-beta; TNF-α, tumor necrosis factor-alpha; IL-6, interleukin 6; IFN-γ, interferon gamma; IL-1β, interleukin 1 beta.
DOR, δ opioid receptor; MOR, μ opioid receptor; NPCs, neural precursor cells; EGL, external granular layer; hCB- and hPB-CD34+ cells, human CD34+ hematopoietic stem cells obtained from umbilical cord and peripheral blood, respectively; phospho-MAPK, phosphorylated form of mitogen-activated protein kinase; phospho-p38, phosphorylated form of p38 mitogen-activated protein kinase; U50,488, trans-3,4-dichloro-N-methyl-N[2-(1-pyrolidinyl)cyclohexyl] benzeneacetamide methanesulfonate; Nor-BNI, nor-binaltorphimine; KOR, κ opioid receptor; NSCs, neural stem cells; DHT, dihydrotestosterone; p53, tumor protein p53; NOP, nociceptin/orphanin FQ receptor; SSCs, spermatogonial stem cells; DADLE, [D-Ala2, D-Leu5]-enkephalin; hUCB-MSCs, human umbilical cord blood-derived mesenchymal stem cells; Bcl-2, B-cell lymphoma 2; Bax, Bcl-2-associated X protein; Bad, Bcl-2-associated death promoter; PI3K, phosphoinositide 3-kinase; Akt, protein kinase B; H2O2, hydrogen peroxide; ROS, reactive oxygen species; AP sites, apurinic/apyrimidinic sites; UPR, unfolded protein response; IRE-1α, inositol-requiring enzyme 1 alpha; Bip, binding immunoglobulin protein; PERK, protein kinase R-like endoplasmic reticulum kinase; ATF-4, activating transcription factor 4; CHOP, C/EBP homologous protein; H/R, hypoxia/reperfusion; CoCl2, cobalt chloride; ATF-6, activating transcription factor 6; IL-4, interleukin 4; IL-10, interleukin 10; TGF-β, transforming growth factor-beta; TNF-α, tumor necrosis factor-alpha; IL-6, interleukin 6; IFN-γ, interferon gamma; IL-1β, interleukin 1 beta.

2. Endogenous Opioids modulate Stem Cell Differentiation

The ability to differentiate is one of the most important properties of SCs. The following Table summarizes the results obtained from the studies demonstrating the involvement of endogenous or synthetic opioids in SC commitment and/or differentiation, in particolar neural, hematopoietic, vascular and cardiac stem cell differentiation (table complete of all references is published in [1]Table 2).

Table 1. Effects of endogenous opioids on stem cell proliferation and stress response.

Opioids/Agonists

Opioids/Agonists

Pre-Treatment

Pre-Treatment

Antagonists

Antagonists

Opioid Receptor

Opioid Receptor

Cell Type

Cell Type

Biological Effects

Biological Effects

Neural Differentiation

DAMGO

U69,593

(10−7–10−6 M)

RA neural

induction

 

KOR-1

MOR-1

ESCs

(from mouse blastocyst)

ESCs

(from ICM of 3.5-day-old mouse)

MOR-1 and KOR-1 were expressed

in undifferentiated ESCs

and in RA-induced ESC-derived NPCs.

Both opioids induced ESC neuronal differentiation

activating ERK pathway.

DAMGO

U69,593

(10−6 M)

RA neural

induction

 

KOR

MOR

ESCs

(from mouse blastocyst)

Opioids reduced neurogenesis and astrogenesis

in RA-induced ESC-NPCs

through p38 MAPK and ERK pathways, respectively.

Opioids stimulated oligodendrogenesis via both ERK and

p38 signaling pathways.

DAMGO

SNC80

U50,488H

(10−7–3 × 10−5 M)

 

 

DOR

KOR

MOR

MEB5

(from 14.5-day-old mouse forebrains)

Only the DOR agonist SNC80 promoted neural differentiation.

 

Neural

induction

 

 

Human

USSCs and BM-MSCs

Neural induction increased enkephalinergic markers

(Ikaros, CREBZF, and PENK), especially

in USSC-derived neuron-like cells.

PDYN expression was enhanced

in USSC-derived neuron-like cells.

Dynorphin-A

U50,488H

(10−6 M)

Neural

induction with opioid/

agonist

Nor-BNI

(10−5 M)

KOR

NSCs

(from 8-week-old

mouse hippocampus)

NSCs expressed high levels of KOR.

Opioid treatment decreased neurogenesis by modulating Pax6/Neurog2/NeuroD1 activities

via upregulation of miR-7a expression.

Opioid treatment did not alter astrogenesis

and oligodendrogenesis.

Opioid treatment did not affect proliferation and apoptosis.

Morphine

(10−5 M)

Neural

induction

with opioid

 

 

NSCs

(from postnatal

p0 mouse hippocampus)

Morphine promoted neurogenesis,

increased apoptosis, and decreased total cell number

during the later stages of differentiation.

Morphine increased

glutathione/glutathione disulfide ratio and decreased S-adenosylmethionine/S-adenosylhomocysteine ratio.

Hematopoietic and Vascular Differentiation

Beta-endorphin

(1 to 1000 ng/mL)

Dynorphin

(1 ng/mL)

Leu-enkephalin

Met-enkephalin

(100 ng/mL)

EP (0.4 U/mL) induced erythropoiesis

with opioid

 

 

 

Mouse BM progenitor cells

 

In the presence of EP, opioids enhanced BM progenitor

differentiation into CFU-e.

TRK820

U50,488H

(10−5 M)

Vascular induction

 

KOR

ESstA-ROSA

(engineered

mouse ESCs)

KOR agonists inhibited EC differentiation and

3D vascular formation in ESC-derived vascular progenitor cells.

KOR agonists decreased the expression of

Flk1 and NRP1 through inhibition of cAMP/PKA signaling in vascular progenitor cells.

Met-enkephalin

(10−14 to 10−8 M)

 

 

KOR

DOR

Mouse BM

progenitor cells

Met-enk upregulated the expression

of KOR and DOR in BM-derived DCs.

Met-enk induced BM-derived DCs

to differentiate mainly towards the mDC subtype.

Met-enk increased the expression

of MHC class II molecules and the release of

pro-inflammatory cytokines (IL-12p70, TNF-α).

Hematopoietic and Vascular Differentiation

Morphine

(10−4 M)

 

Naloxone

(10−4 M)

 

Rat NSCs

Morphine reduced survival and clonogenicity,

negatively affecting tubulogenesis properties of NSCs

by the inhibition of neuro-angiogenesis trans-differentiation.

Cardiac Differentiation

Dynorphin-B

(10−9 to 10−6 M)

DMSO 1%

 

KOR

Mouse ESCs

DMSO increased PDYN gene expression and dynorphin-B

synthesis and secretion.

Dynorphin-B elicited GATA-4 and Nkx-2.5 gene transcription and enhanced gene and protein expression of α-MHC and MLC-2V.

Dynorphin-B

(10−8 to 10−6 M)

Cardiac

induction

 

KOR

GTR1-ESCs

(engineered mouse ESCs)

ESC plasma membranes and nuclei expressed

KOR-specific opioid binding sites.

ESC-derived cardiomyocytes showed an

increase in dynorphin-B around the nucleus.

Dynorphin-B induced an increase of GATA-4,

Nkx-2.5, and PDYN gene expressions

and promoted cardiogenesis by PKC signaling.

 

HBR cardiac induction

(0.75 mg/mL)

 

 

GTR1-ESCs

(engineered mouse ESCs)

HBR-induced ESC-derived cardiomyocytes enhanced

GATA-4, Nkx-2.5, and PDYN gene transcriptions and the

intracellular level of dynorphin-B.

 

ELF-MF

exposition during

cardiac

induction

(50 Hz, 0.8 m Trms)

 

 

GTR1-ESCs

(engineered mouse ESCs)

ELF-MF spontaneously induced cardiogenesis,

upregulating GATA-4, Nkx-2.5, and PDYN gene expression

and enhancing intracellular levels and secretion of dynorphin-B.

Cardiac Differentiation

 

REAC

exposition during

cardiac

induction

(MF of 2.4 and 5.5 GHz)

 

 

Mouse ESCs and

human ASCs

Both SCs committed to cardiac lineage and exposed to REAC

increased the expression of GATA-4, Nkx-2.5, and PDYN gene.

Dynorphin-B

(10−7 M)

Cardiac

Cardiac

induction

 

DOR

KOR

Mouse ESCs

Both DOR and KOR increased during ESC differentiation.

Dynorphin-B inhibited Oct-4

and increased Nkx-2.5 gene expression.

Dynorphin-A, met-enkephalins, and leu-enkephalins

did not affect ESC differentiation.

Ref.

induction

 

 

CPCs

(from 11.5-day-old

embryonic mouse

ventricles)

Dynorphin B promoted CPC differentiation into cardiomyocytes.

Dynorphin-A

Dynorphin-B

Met-enkephalins

Leu-enkephalins

(10−5 M)

Neural Differentiation
DAMGO

U69,593

(10−7–10−6 M)
RA neuralinduction KOR-1

MOR-1
ESCs

(from mouse blastocyst)

ESCs

(from ICM of 3.5-day-old mouse)
MOR-1 and KOR-1 were expressed

in undifferentiated ESCs

and in RA-induced ESC-derived NPCs.

Both opioids induced ESC neuronal differentiation

activating ERK pathway.
[19]
DAMGO

U69,593

(10−6 M)
RA neural

induction
 KOR

MOR
ESCs

(from mouse blastocyst)
Opioids reduced neurogenesis and astrogenesis

in RA-induced ESC-NPCs

through p38 MAPK and ERK pathways, respectively.

Opioids stimulated oligodendrogenesis via both ERK and

p38 signaling pathways.
[20]
DAMGO

SNC80

U50,488H

(10−7–3 × 10−5 M)
  DOR

KOR

MOR
MEB5

(from 14.5-day-old mouse forebrains)
Only the DOR agonist SNC80 promoted neural differentiation.[21]
 Neural

induction
  Human

USSCs and BM-MSCs
Neural induction increased enkephalinergic markers

(Ikaros, CREBZF, and PENK), especially

in USSC-derived neuron-like cells.

PDYN expression was enhanced

in USSC-derived neuron-like cells.
[22]
Dynorphin-A

U50,488H

(10−6 M)
Neural

induction with opioid/

agonist
Nor-BNI

(10−5 M)
KORNSCs

(from 8-week-old

mouse hippocampus)
NSCs expressed high levels of KOR.

Opioid treatment decreased neurogenesis by modulating Pax6/Neurog2/NeuroD1 activities

via upregulation of miR-7a expression.

Opioid treatment did not alter astrogenesis

and oligodendrogenesis.

Opioid treatment did not affect proliferation and apoptosis.
[23]
Morphine

(10−5 M)
Neural

induction

with opioid
  NSCs

(from postnatal

p0 mouse hippocampus)
Morphine promoted neurogenesis,

increased apoptosis, and decreased total cell number

during the later stages of differentiation.

Morphine increased

glutathione/glutathione disulfide ratio and decreased S-adenosylmethionine/S-adenosylhomocysteine ratio.
[24]
Hematopoietic and Vascular Differentiation
Beta-endorphin

(1 to 1000 ng/mL)

Dynorphin

(1 ng/mL)

Leu-enkephalin

Met-enkephalin

(100 ng/mL)
EP (0.4 U/mL) induced erythropoiesis

with opioid
  Mouse BM progenitor cellsIn the presence of EP, opioids enhanced BM progenitor

differentiation into CFU-e.
[25]
TRK820

U50,488H

(10−5 M)
Vascular induction KORESstA-ROSA

(engineered

mouse ESCs)
KOR agonists inhibited EC differentiation and

3D vascular formation in ESC-derived vascular progenitor cells.

KOR agonists decreased the expression of

Flk1 and NRP1 through inhibition of cAMP/PKA signaling in vascular progenitor cells.
[26]
Met-enkephalin

(10−14 to 10−8 M)
  KOR

DOR
Mouse BM

progenitor cells
Met-enk upregulated the expression

of KOR and DOR in BM-derived DCs.

Met-enk induced BM-derived DCs

to differentiate mainly towards the mDC subtype.

Met-enk increased the expression

of MHC class II molecules and the release of

pro-inflammatory cytokines (IL-12p70, TNF-α).
[27]
Hematopoietic and Vascular Differentiation
Morphine

(10−4 M)
 Naloxone

(10−4 M)
 Rat NSCsMorphine reduced survival and clonogenicity,

negatively affecting tubulogenesis properties of NSCs

by the inhibition of neuro-angiogenesis trans-differentiation.
[28]
Cardiac Differentiation
Dynorphin-B

(10−9 to 10−6 M)
DMSO 1% KORMouse ESCsDMSO increased PDYN gene expression and dynorphin-B

synthesis and secretion.

Dynorphin-B elicited GATA-4 and Nkx-2.5 gene transcription and enhanced gene and protein expression of α-MHC and MLC-2V.
[29]
Dynorphin-B

(10−8 to 10−6 M)
Cardiac

induction
 KORGTR1-ESCs

(engineered mouse ESCs)
ESC plasma membranes and nuclei expressed

KOR-specific opioid binding sites.

ESC-derived cardiomyocytes showed an

increase in dynorphin-B around the nucleus.

Dynorphin-B induced an increase of GATA-4,

Nkx-2.5, and PDYN gene expressions

and promoted cardiogenesis by PKC signaling.
[30][31]
 HBR cardiac induction

(0.75 mg/mL)
  GTR1-ESCs

(engineered mouse ESCs)
HBR-induced ESC-derived cardiomyocytes enhanced

GATA-4Nkx-2.5, and PDYN gene transcriptions and the

intracellular level of dynorphin-B.
[32]
 ELF-MF

exposition during

cardiac

induction

(50 Hz, 0.8 m Trms)
  GTR1-ESCs

(engineered mouse ESCs)
ELF-MF spontaneously induced cardiogenesis,

upregulating GATA-4, Nkx-2.5, and PDYN gene expression

and enhancing intracellular levels and secretion of dynorphin-B.
[33]
Cardiac Differentiation
 REAC

exposition during

cardiac

induction

(MF of 2.4 and 5.5 GHz)
  Mouse ESCs and

human ASCs
Both SCs committed to cardiac lineage and exposed to REAC

increased the expression of GATA-4Nkx-2.5, and PDYN gene.
[34][35]
Dynorphin-B

(10−7 M)
Cardiac

induction
  CPCs

(from 11.5-day-oldembryonic mouseventricles)
Dynorphin B promoted CPC differentiation into cardiomyocytes.[36]
Dynorphin-A

Dynorphin-B

Met-enkephalins

Leu-enkephalins

(10−5 M)
Cardiac

induction
 DOR

KOR
Mouse ESCsBoth DOR and KOR increased during ESC differentiation.

Dynorphin-B inhibited Oct-4

and increased Nkx-2.5 gene expression.

Dynorphin-A, met-enkephalins, and leu-enkephalinsdid not affect ESC differentiation.
[37]

 

DAMGO, [D-Ala2,MePhe4,Glyol5]-enkephalin; U69,593, N-methyl-2-phenyl-N-[(5R,7S,8S)-7-(pyrrolidin-1-yl)-1-oxaspiro[4.5]dec-8-yl]acetamide; RA, retinoic ac-id; KOR-1, κ opioid receptor isoform 1; MOR-1, μ opioid receptor isoform 1; ESCs, embryonic stem cells; ICM, inner cell mass; NPCs, neural progenitor cells; ERK, extracellular signal-regulated kinase; p38 MAPK, p38 mitogen-activated protein kinase; SNC80, [(+)-4-[(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide]; U50,488H, (–)-trans-(1S,2S)-U-50488 hydrochlo-ride; Nor-BNI, nor-binaltorphimine; DOR, δ opioid receptor; MEB5, multipotent neural stem cells; USSCs, unrestricted somatic stem cells; BM-MSCs, bone mar-row mesenchymal stem cells; Ikaros, IKAROS family zinc finger 1; CREBZF, CREB/ATF bZIP transcription factor; PENK, proenkephalin; PDYN, prodynorphin; NSCs, neural stem cells; Pax6, paired box 6; Neurog2, neurogenin 2; NeuroD1, neuronal differentiation 1; leu-enkephalin, leucine-enkephalin; met-enkephalin, methionine-enkephalin; EP, erythropoietin; CFU-e, colony-forming unit-erythroid; TRK820, 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furyl) acrylamido]morphinan hydrochloride; EC, endothelial cell; Flk1, fetal liver kinase 1/VEGF receptor 2; NRP1, neuropilin 1; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; DCs, dendritic cells; mDCs, myeloid dendritic cells; MHC, major histocompatibility complex; TNF-α, tumor necrosis factor alpha; IL-12p70, active heteodimer of interleukin 12. p53, tumor protein p53; DMSO, dimethyl sulfoxide; GATA-4, GATA binding protein 4; Nkx-2.5, Nkx homeobox 5; α-MHC, α-myosin heavy chain; MLC-2V, myosin light chain; PKC, protein kinase C; HBR, hyaluronan mixed esters of butyric and retinoic acids; ELF-MF, extremely low frequency magnetic fields; REAC, radio electric asymmet-ric conveyer; ASCs, adipose-derived mesenchymal stem cells; SCs, stem cells; CPCs, cardiac progenitor cells; Oct-4, octamer-binding transcription factor 4.

 

23. Conclusion

Overall, opioidergic systems encompass a wide-ranging variety of bioactive peptides, providing multi-layered control of major determinants in cell and SC biology. Compounding their biological complexity, opioid peptides were found to act as “one component–multiple target conductors”, which often led to the observation of opposite effects on the same outcome (i.e., proliferation or differentiation) depending on the spe-cific SC target towards which activity was probed.

Nevertheless, deciphering the complexity of the informational cues associated with opioid peptide-mediated responses may hold promise for intriguing future developments. These future perspectives involve the potential for the timely and synergistic use of naturally occurring and synthetic opioids for the fine tuning of remarkable develop-ments in regenerative medicine, including differentiation, proliferation, multicellular cross talk, inflammation, and tissue remodelling.

 

All information of this Encyclopedia entry are part of the complete published manuscript:[1]

 

 

 

 

 

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