Interaction of β‐funaltrexamine with [3H]cycloFOXY binding in rat brain: Further evidence that β‐FNA alkylates the opioid receptor complex

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Abstract
β‐Funaltrexamine (β‐FNA) is an alkylating derivative of naltrexone. In addition to acting as an irreversible inhibitor of μ‐receptor‐mediated physiological effects, intracerebroventricular (i.c.v.) administration of β‐FNA to rat attenuates the ability of selective δ receptor antagonists and naloxne to reverse δ receptor‐mediated effects. Moreover, recent work demonstrated that i.c.v. administration of β‐FNA alters the conformation of the opioid receptor complex, as inferred by a decrease in the Bmax of the lower affinity [3H][D‐ala2, D‐leu5]enkephalin binding site. Consistent with the decreased potency of naloxone as an inhibitor of δ receptor mediated effects, β‐FNA doubled the naloxone IC50 for displacing [3H][D‐ala2, D‐leu5]enkephalin from its lower affinity binding site. These data collectively support the hypothesis that the opioid receptor complex postulated to mediate μ‐δ interactions in vivo is identical to the opioid receptor complex as defined by vitro ligand binding studies. A direct prediction of this hypothesis is that β‐FNA should increase the Kd of antagonists for the μ binding site (μcx) of the receptor complex. The data reported in this paper demonstrate that β‐FNA doubled the IC50 of the potent narcotic antagonist, 6‐desoxy‐6β‐fluoronaltrexone (cycloFOXY) for displacing [3H][D‐ala2, D‐leu5]enkephalin from its lower affinity binding site, and doubled the Kd of [3H]cycloFOXY for its μ binding site, providing additional data that the μ binding site labeled by [3H]cycloFOXY is the μ binding site of the opioid receptor complex. β‐FNA also altered the K binding site labeled by [3H]cycloFOXY, and when administered intrathecally to mice, β‐FNA produced a longlasting antinociception in the acetic acid writhing test.