Profound Spinal Tolerance after Repeated Exposure to a Highly Selective μ-Opioid Peptide Agonist: Role of δ-Opioid Receptors

Abstract

Recent studies suggest that ␦-opioid receptors play a role in the development of opioid tolerance and led us to hypothesize that highly selective -opioid agonists may produce less tolerance.]DALDA) has extraordinary selectivity for -receptors (K i ␦

Tolerance develops in spinal cord, but not in brain with chronic [Dmt1]DALDA treatment

“…1000 times the original AD 50 . Clearly, our data as well as those of Zhao et al (2002), show that tolerance develops very differently to [Dmt 1 ]DALDA in the spinal cord and brain. In an attempt to understand these differences, we determined the expression of the three major opioid receptor genes and the three major opioid peptide precursors in brain and spinal cord.…”

“…Another group reported a somewhat similar study of chronic treatment with [Dmt 1 ]DALDA (Zhao et al, 2002). They also found that tolerance to spinal drug administration was much greater than to i.c.v.…”

“…Their use of [Dmt 1 ]DALDA may account for their observation that tolerance at the spinal level was measurable, whereas it was not in our study using DAMGO. Zhao et al (2002) also reported a much lower degree of cross-tolerance of morphine (s.c.) than we did to [Dmt 1 ]DALDA, about 15-fold. At least part of the discrepancy may be due to their use of a somewhat weaker dosing regimen.…”

“…However, the very large degree of tolerance developed when [Dmt 1 ]DAL-DA was administered systemically or to the spinal cord suggests that this would be a good system in which to reinvestigate this question. Zhao et al (2002) reported that the B max of tritiated [Dmt 1 ]DALDA binding was decreased by 30-35%, though this change was observed in both the brain and spinal cord of animals treated chronically with this drug.…”

Cell-Permeable, Mitochondrial-Targeted, Peptide Antioxidants

“…Furthermore, analgesia studies in mice suggest that SS-02 readily penetrates the blood-brain-barrier after subcutaneous administration. 31 This has also been confi rmed by the detection of …”