PubMed · 7868340
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L Robbins. 1995. Analgesic rebound headaches.. https://doi.org/10.1111/j.1526-4610.1995.hed3501050_6.x
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The affinity, selectivity and antinociceptive properties of 5 beta-methyl-14 beta-(p-chlorocinnamoylamino)-7,8-dihydromorphinone (MET-Cl-CAMO) and N-cyclopropyl-methyl-5 beta-methyl-14 beta-(p-chlorocinnamoylamino)-7, 8-dihydronormorphinone (N-CPM-MET-Cl-CAMO) for the multiple opioid receptors were characterized. In competition binding assays using bovine striatal membranes, both compounds inhibited the binding of 0.25 nM [3H][D-Ala2, (Me)-Phe4,Gly(ol)5]enkephalin (DAMGO) with IC 50 values of less than 2 nM. Preincubation of membranes with MET-CI-CAMO and N-CPM-MET-Cl-CAMO produced a concentration-dependent, wash-resistant inhibition of mu-opioid receptor binding. Saturation binding experiments with N-CPM-MET-Cl-CAMO showed a reduction in the number of mu-opioid binding sites without a change in affinity. In the mouse 55 degrees C warm-water tail-flick assay, neither MET-Cl-CAMO nor N-CPM-MET-Cl-CAMO at doses up to 100 nmol produced antinociception after intracerebroventricular administration, but morphine-induced antinociception was antagonized in a time- and dose-dependent manner by both compounds. The antagonism produced by 1 nmol of either MET-Cl-CAMO or N-CPM-MET-Cl-CAMO reached a maximal effect after 24 h, and lasted up to 48 h. Analgesia mediated by delta- or kappa-opioids was not altered by either compound. In summary, the data suggest that MET-Cl-CAMO and N-CPM-MET-Cl-CAMO are long-term, mu-opioid receptor antagonists, devoid of agonist properties in the mouse tail-flick assay, and that N-CPM-MET-Cl-CAMO may produce its antagonistic effects by binding irreversibly to the mu-opioid receptor.
The effect of a mu-opioid receptor irreversible antagonist on the development of tolerance to fentanyl was determined in mice. Mice were injected with saline or clocinnamox (3.2 mg/kg, i.p.) and 4 h later mice implanted s.c. with a placebo pellet or an osmotic minipump that infused fentanyl (0.165 mg/kg per day) for 3 days. Fentanyl pumps and placebo pellets were removed on the third day following implantation and 4 h later mu-opioid receptor saturation binding studies in whole brain ([3H][D-Ala2,MePhe4,Gly-ol5]enkephalin: DAMGO) or fentanyl analgesic dose-response studies (tailflick assay) were conducted. Fentanyl infusions and clocinnamox both significantly reduced the potency of fentanyl by 2.8- and 2.4-fold, respectively. When fentanyl and clocinnamox were administered together, a significant 5.0-fold reduction in fentanyl potency relative to the saline-placebo group was observed, which represents an additive effect of clocinnamox and fentanyl. The ED50 of fentanyl in clocinnamox-treated mice was shifted 2.1-fold by fentanyl infusion relative to the clocinnamox-placebo group. This is comparable to the 2.8-fold shift in the ED50 produced by fentanyl infusion in saline-treated mice. In binding studies, fentanyl produced a small (-9%) reduction in Bmax, while clocinnamox significantly reduced (-41%) mu-opioid receptor density without altering affinity (Kd). In the clocinnamox-fentanyl group, there was a 50% reduction in Bmax, which is similar to the additive effect observed in analgesia studies. These data indicate that changes in mu-opioid receptor density prior to the development of tolerance to fentanyl do not impact on the magnitude of tolerance.
Human recombinant interleukin-2 (IL-2) has been showed to exert an analgesic effect and some experiments suggested that opioid receptors were involved. Because the aromatic residues at the N-termini of opioid peptides are crucial for their binding to the opioid receptors, all nine aromatic residues in IL-2 were mutated by site-directed mutagenesis and both the analgesic activity and the immune activity of the wild-type and mutated IL-2 were tested. The result indicated that there exists a putative analgesic function domain in IL-2, in which Phe44, Tyr45, Tyrl07, and Phell7 were essential. These four residues are located close together at the tertiary structure level of IL-2.