Microglial IL-10 and β-endorphin expression mediates gabapentinoids antineuropathic pain

Gabapentinoids are recommended first-line treatments for neumpathic pain. They are neuronal voltage-dependent calcium channel alpha 2 delta-1 subunit ligands and have been suggested to attenuate neuropathic pain via interaction with neuronal alpha 2 delta-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 mu g (or 176.9, 38.9 and 7.2 nmol) and E-max values of 66%, 61% and 65% MPE respectively for mechanical allodynia. Intrathecal gabapentinoids stimulated spinal mRNA and protein expression of IL-10 and beta-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 beta-endorphin in male/female neuropathic and male sham rats. Treatment with gabapentin, pregabalin and mirogabalin specifically upregulated IL-10 and beta-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 mu M and 34.7, 13.3 and 2.8 mu M respectively. Pretreatment with intrathecal microglial metabolic inhibitor minocycline, IL-10 antibody, beta-endorphin antiserum or mu-opioid receptor antagonist CTAP (but not kappa- or delta-opioid receptor antagonists) suppressed spinal gabapentinoids-inhibited mechanical allodynia. Immunofluorescence staining exhibited specific alpha 2 delta-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 beta-endorphin.

Automated summary

Gabapentinoids alleviate neuropathic pain by stimulating the expression of spinal microglial IL-10 and consequent beta-endorphin.