Table 1.
Preclinical and clinical trials focusing on microglial activation and polarization for pain treatment
| No | Model/disease | Therapeutic approach | Targets/mechanism of action | M1 state | M2 state | Results | References |
|---|---|---|---|---|---|---|---|
| 1 | Collagen-induced arthritis pain rat model (in vivo) | A-438079 | P2X7 antagonist | Down-regulation: IL-1β | – |
Attenuated mechanical allodynia Reduced microgliosis |
(Nieto et al. 2016) |
| 2 | LPS-induced injury in microglial BV-2 cells (in vitro) | Crotalphine | Decreased LPS-induced CD86 expression and elevated CD206 expression | Down-regulation: CD86 | Up-regulation: CD206 |
Mitigates central neuroinflammation Analgesic effect |
(Lopes et al. 2022) |
| 3 | Bone cancer pain mouse model (in vivo) | Dehydrocorydaline | Inhibit M1 phenotype, and increase M2 polarization | Down-regulation: iNOS, CD16/32, IL-1β | Up-regulation: Arg-1, CD206, IL-10 |
Suppressed inflammatory response Antinociceptive effect |
(Huo et al. 2018) |
| 4 | Chronic constriction injury rat model of neuropathic pain (in vivo) | Kaempferol | Suppression of microglial activation and shifting the M1 to M2 | Down-regulation: IL-1β, IL-6, LPS, TNF-ɑ, PGE2 | Up-regulation: IL-10 | Analgesic action | (Chang et al. 2022) |
| 5 | LPS-induced injury in microglial BV-2 cells (in vitro) | kaempferol | Inhibition of TLR4/NF-κB signaling pathway | Down-regulation: IL-1β,TNF-ɑ, CD32, iNOS | Up-regulation: IL-10, Arg-1, CD206 | Pain reduction | (Chang et al. 2022) |
| 6 | Chronic constriction injury rat model of neuropathic pain (in vivo) | Dual-specificity phosphatase-1 (DUSP1) | Inhibition of the MAPK signaling | Down-regulation | Up-regulation | Increased pain threshold | (Wang et al. 2021) |
| 7 | Chronic constriction injury mouse model of neuropathic pain (in vivo) | IL-4 | Shifted microglia from the M1 to M2 phenotype | Down-regulation: IL-1β, TNF, iNOS | Up-regulation: IL-10, Arg-1, Ym1 |
Reduced neuropathy-induced mechanical hypersensitivity Analgesic actions |
(Celik et al. 2020) |
| 8 | Bone cancer pain rat model (in vivo) | Minocycline | Inhibition of microglia activation | Down-regulation: CD86, IL-1β, TNF-α | Up-regulation: CD206, IL-10 | Attenuated mechanical allodynia | (Dai et al. 2019) |
| 9 | Spinal cord injury rat model (in vivo) | Propentofylline | Prevention of glial activation | – | – | Increased the mechanical allodynia threshold | (Gwak et al. 2008) |
| 10 | Bone cancer pain rat model (in vivo) | Propentofylline | Inhibition of microglia activation | Down-regulation: IL-1β, IL-6, TNF-α | – | Antiallodynic action | (Yao et al. 2011) |
| 11 | Peripheral nerve injury rat model (in vivo) | Propentofylline | Suppression of microglial activation | – | – | Attenuated nerve injury-induced mechanical allodynia | (Tawfik et al. 2007) |
| 12 | Monoarthritis pain rat model (in vivo) | Propentofylline | Glial inhibitor | – | – | Antinociceptive effect | (Morales et al. 2012) |
| 13 | Cancer-induced bone pain rat model (in vivo) | Naringenin | Down-regulation of NF-κB-mediated p65 expression and activation of AMPK/PGC-1α signaling pathway | Down-regulation: CD86, iNOS | Up-regulation: CD206, Arg-1 | Antinociceptive effects | (Ge et al. 2022) |
| 14 | Spinal nerve ligation pain rat model (in vivo) | Minocycline | Mitigation of microglial activation | Down-regulation: IL-1β, IL-6 | Up-regulation: IL-10 | Inhibition of neuropathic pain | (Burke et al. 2014) |
| 15 | LPS and IFN-γ-induced injury in BV-2 Microglia Cells (in vitro) | Naltrexone | Toll-like receptor 4 antagonism | Down-regulation: iNOS | Up-regulation: CD206 | Reduction of neuroinflammation | (Kučić et al. 2021) |
| 16 | Chronic compression injury rat model (in vivo) | Botulinum toxin type A | Inhibition of P2X7R expression | Down-regulation: CD68 | Up-regulation: CD206 |
Elevation of pain threshold Relief of neuropathic pain |
(Gui et al. 2020) |
| 17 | LPS-stimulated HAPI rat microglial cells (in vitro) | Botulinum toxin type A | Inhibition of P2X7R expression | Down-regulation: iNOS, TNF-α, IL-6 | Up-regulation: Arg-1, IL-10 |
Decreased P2X7 protein level Enhancement of M2 polarization |
(Gui et al. 2020) |
| 18 | Neuropathic pain or fibromyalgia (clinical trial) | Minocycline | Attenuation of microglial activation | – | – | Reduction in number of tender points | (Miwa 2021) |
| 19 | Multiple continuous stress rat model of chronic fatigue syndrome and fibromyalgia (in vivo) | Minocycline | Suppression of microglial activation | – | – | Attenuation of allodynia and hyperalgesia | (Yasui et al. 2014) |
| 20 | Fibromyalgia (clinical trial) | Naltrexone | Inhibition of microglia activity | – | – |
Reduction in fibromyalgia symptoms Improvement in mechanical and heat pain thresholds |
(Younger and Mackey 2009) |
| 21 | Fibromyalgia (clinical trial) | Naltrexone | Anti-inflammation through modulation of M1/M2 polarization | Down-regulation: IL-1β, IL-6, IL-12, TNF-α | – |
Decrease nociception, allodynia, and hyperalgesia Reduction of fibromyalgia-associated pain |
(Parkitny and Younger 2017) |
| 22 | Widespread muscle pain rat model of fibromyalgia (in vivo) | IL-5 | promoting M2 response to counteract the M1 response | – | UP-regulation: CD206 | Reduction of hyperalgesia | (Merriwether et al. 2021) |
| 23 | Fibromyalgia (clinical trial) | Aquatic exercise | Anti-inflammation through modulation of pro- and anti-inflammatory cytokine production | Down-regulation: TNF-α, IL-6, IL-1β | Up-regulation: IL-10 | Improvement of fibromyalgia patients’ quality of life | (Ortega et al. 2012) |
| 24 | Reserpine rat model of fibromyalgia (in vivo) | Brilliant Blue G | P2X7R antagonist and inhibition of microglial activation | Down-regulation: IL-1β, IL-18 | – | Attenuation of mechanical and thermal hyperalgesia and allodynia | (D’amico et al. 2021) |
| 25 | Reserpine rat model of fibromyalgia (in vivo) | Infliximab | Reduced P2X7R expression and its downstream p38-MAPK, and inhibition of microglial activation | Down-regulation: IL-1β, IL-6, TNF-α | – | Reduction of fibromyalgia-associated pain sensitization | (Cordaro et al. 2022) |
| 26 | Reserpine rat model of fibromyalgia (in vivo) | Galantamine | Shifted microglia from M1 to M2 phenotype | Down-regulation: iNOS, CD86 | Up-regulation: Arg-1, CD163 | Analgesic and anti-neuroinflammatory effects | (Atta et al. 2023) |
| 27 | Fibromyalgia (clinical trial) | Dextromethorphan | Inhibition of microglial activation | – | – | Mitigation of fibromyalgia-associated pain | (Mueller et al. 2021) |
| 28 | Fibromyalgia (clinical trial) | Milnacipran | Reduction of glial activation | – | – | Analgesic properties | (Natelson et al. 2015) |
| 29 | Stress-induced irritable bowel syndrome rat model (in vivo) | Minocycline | Inhibition of p38-MAPK pathway and subsequent microgliosis | – | – | Alleviated visceral pain hypersensitivity | (Yuan et al. 2020) |
| 30 | Colorectal distension-induced irritable bowel syndrome rat model (in vivo) | Minocycline | Suppression of the activated microglia-dependent inhibition of GABAergic neuronal activity | – | – | Elevation of visceral pain threshold | (Ji et al. 2022) |
| 31 | Fibromyalgia (clinical trial) | Cannabidiol | Reduction of microglia activation and M1 polarization | – | – | Analgesic effects | (NCT05283161 2022) |