Combined glia inhibition and opioid receptor agonism afford highly potent analgesics without tolerance
2019
Commonly prescribed opioid analgesics produce tolerance upon chronic use due in part to induction of hyperalgesia. Given that two reported bivalent ligands (MMG22 and MCC22) produce potent antinociception without tolerance only in inflamed mice, we have investigated the possible cellular and receptor targets of these ligands. The selective microglia inhibitors, minocycline and SB290157, antagonized intrathecal (i.t.) MCC22 antinociception orders of magnitude more potently than MMG22, suggesting that MCC22 selectively targets activated microglia. The astrocyte toxin, l-α-aminoadipic acid antagonized MMG22 antinociception 126-fold without reducing the potency of MCC22, indicating that activated astrocytes are targets of MMG22. MK-801 and Ro25-6981 antagonism of MMG22 antinociception, but not MCC22, is consistent with selective inhibition of activated NMDAR in astrocytes. The antinociception produced by i.t. MMG22 or MCC22 were both antagonized by the selective mu opioid receptor antagonist, β-FNA, implicati...
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