Differential inhibitory effects of μ-opioids on substance P- and capsaicin-induced nociceptive behavior in mice

Abstract The antinociceptive mechanisms of the selective μ-opioid receptor agonists [ d -Ala 2 ,NMePhe 4 ,Gly(ol) 5 ]enkephalin (DAMGO), H-Tyr- d -Arg-Phe-β-Ala-OH (TAPA) or H-Tyr- d -Arg-Phe-β-Ala-NH 2 (TAPA-NH 2 ) against substance P (SP)- or capsaicin-elicited nociceptive behaviors was investigated in mice. DAMGO, TAPA or TAPA-NH 2 given intrathecally inhibited the nociceptive behaviors elicited by intrathecally administered SP or capsaicin, and these antinociceptive effects were completely eliminated by intrathecal co-administration with d -Phe-Cys-Tyr- d -Trp-Orn-Thr-Pen-Thr-NH 2 (CTOP), a selective μ-opioid receptor antagonist. Pretreatment subcutaneously with naloxonazine, a selective μ 1 -opioid receptor antagonist, partially attenuated the antinociceptive effect of TAPA-NH 2 , but not DAMGO and TAPA, against SP. However, the antinociception induced by TAPA, but not DAMGO and TAPA-NH 2 , against capsaicin was significantly inhibited by naloxonazine. On the other hand, co-administration intrathecally with Tyr- d -Pro-Trp-Gly-NH 2 ( d -Pro 2 -Tyr-W-MIF-1), a selective μ 2 -opioid receptor antagonist, significantly attenuated the antinociceptive effects of DAMGO, but not TAPA and TAPA-NH 2 , against capsaicin, while the antinociceptions induced by three opioid peptides against SP were significantly inhibited by d -Pro 2 -Tyr-W-MIF-1. These results suggest that differential inhibitory mechanisms on pre- and postsynaptic sites in the spinal cord contribute to the antinociceptive effects of the three μ-opioid peptides.