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. |
[77] | |
| 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. |
[78] | ||
| 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. |
[81] | |
| Morphine | MOR | NSCs | Theoretical hypothesis: since morphine reduces testosterone levels, increases DHT levels, andover-expresses p53 gene, it might prevent NSC proliferation. |
[82] | ||
| 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. |
[88] | |
| Nociceptin | NOP | Mouse SSCs and spermatocytes |
Nociceptin is an upstream Sertoli cell transcription factor that regulates SSC self-renewal and spermatocyte meiosis. |
[90] | ||
| 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. |
[89] | |
| 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). |
[93] |
| 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. |
[98] | |
| 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). |
[21] |
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.