Abstract

Roles of endogenous opioid peptides and their receptors in modulation of the nocifensive responses to formalin in mice were studied. Mice were pretreated i.c.v. or intrathecally (i.t.) with selective opioid receptor antagonists or intrathecally with antisera against endogenous opioid peptides and the nocifensive licking responses to intraplantar injection of formalin (0.5%, 25 μl) were then observed. Pretreatment with the ε-opioid receptor antagonist β-endorphin(1–27) or the selective μ-opioid receptor antagonistd-Phe-Cys-Tyr-Orn-Thr-Pen-Thr-NH₂ (CTOP) given i.c.v. dose dependently enhanced the second, but not the first phase of the nocifensive response. However, i.c.v. pretreatment with the selective δ-receptor antagonist naltrindole or κ-receptor antagonist nor-binaltrophimine did not affect the nocifensive responses. Intrathecal pretreatment with selective δ₁-opioid antagonist 7-benzylidene naltrexamine significantly enhanced both the first and second phases of nocifension. Intrathecal pretreatment with CTOP also increased the second but not the first phase of the nocifension. However, i.t. pretreatment with the selective δ₂-receptor antagonist naltriben or nor-binaltrophimine did not affect the second phase of the nocifension. Intrathecal pretreatment with antiserum against Leu-enkephalin, Met-enkephalin, or dynorphin A(1–17), but not β-endorphin, enhanced only the second phase of nocifensive response to formalin. It is concluded that the blockade of ε- and μ-receptors, but not δ- or κ-receptors, at the supraspinal sites enhanced the second phase of formalin-induced nocifension. In the spinal cord, Leu-enkephalin, and to a lesser extent, Met-enkephalin and dynorphin A(1–17) and μ- and δ₁-opioid receptors, but not δ₂- or κ-opioid receptors, are involved in modulating the feedback inhibition of the second phase of formalin-induced nocifension.