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Microglial IL-10 and β-endorphin expression mediates gabapentinoids antineuropathic pain
- Source :
- Brain, behavior, and immunity. 95
- Publication Year :
- 2020
-
Abstract
- Gabapentinoids are recommended first-line treatments for neuropathic pain. They are neuronal voltage-dependent calcium channel α2δ-1 subunit ligands and have been suggested to attenuate neuropathic pain via interaction with neuronal α2δ-1 subunit. However, the current study revealed their microglial mechanisms underlying antineuropathic pain. Intrathecal injection of gabapentin, pregabalin and mirogabalin rapidly inhibited mechanical allodynia and thermal hyperalgesia, with projected ED50 values of 30.3, 6.2 and 1.5 µg (or 176.9, 38.9 and 7.2 nmol) and Emax values of 66%, 61% and 65% MPE respectively for mechanical allodynia. Intrathecal gabapentinoids stimulated spinal mRNA and protein expression of IL-10 and β-endorphin (but not dynorphin A) in neuropathic rats with the time point parallel to their inhibition of allodynia, which was observed in microglia but not astrocytes or neurons in spinal dorsal horns by using double immunofluorescence staining. Intrathecal gabapentin alleviated pain hypersensitivity in male/female neuropathic but not male sham rats, whereas it increased expression of spinal IL-10 and β-endorphin in male/female neuropathic and male sham rats. Treatment with gabapentin, pregabalin and mirogabalin specifically upregulated IL-10 and β-endorphin mRNA and protein expression in primary spinal microglial but not astrocytic or neuronal cells, with EC50 values of 41.3, 11.5 and 2.5 µM and 34.7, 13.3 and 2.8 µM respectively. Pretreatment with intrathecal microglial metabolic inhibitor minocycline, IL-10 antibody, β-endorphin antiserum or μ-opioid receptor antagonist CTAP (but not κ- or δ-opioid receptor antagonists) suppressed spinal gabapentinoids-inhibited mechanical allodynia. Immunofluorescence staining exhibited specific α2δ-1 expression in neurons but not microglia or astrocytes in the spinal dorsal horns or cultured primary spinal cells. Thus the results illustrate that gabapentinoids alleviate neuropathic pain through stimulating expression of spinal microglial IL-10 and consequent β-endorphin.
- Subjects :
- 0301 basic medicine
Male
Gabapentin
Immunology
Pregabalin
Pharmacology
03 medical and health sciences
Behavioral Neuroscience
chemistry.chemical_compound
0302 clinical medicine
Mirogabalin
Medicine
Animals
Rats, Wistar
Microglia
Endocrine and Autonomic Systems
business.industry
beta-Endorphin
Dynorphin A
Spinal cord
Interleukin-10
Rats
030104 developmental biology
medicine.anatomical_structure
Allodynia
chemistry
Spinal Cord
Hyperalgesia
Neuropathic pain
Neuralgia
Female
medicine.symptom
business
030217 neurology & neurosurgery
medicine.drug
Subjects
Details
- ISSN :
- 10902139
- Volume :
- 95
- Database :
- OpenAIRE
- Journal :
- Brain, behavior, and immunity
- Accession number :
- edsair.doi.dedup.....e657a72f728a48ff8aa1621037adb7c8