[D-Ala2,Leu5,Cys6]enkephalin: Short-term agonist effects and long-term antagonism at delta opioid receptors (original) (raw)
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Analgesia produced by centrally administered DAGO, DPDPE and U50488H in the formalin test
European Journal of Pharmacology, 1988
Three opioid agonists ([D-Ala2,N-MePhe4,Gly-ol 5 ]enkephalin (DAGO), [D-Pen2,D-Pen 5 ]enkephalin (DPDPE) and U50488H) were tested independently for their ability to produce analgesia in the formalin test. These agonists were chosen based upon their ability to act selectively at ~, ~ and ~¢ opioid receptor types respectively. Rats received one intracerebroventricular (i.c.v.) injection of an agonist 20 min after subcutaneous injection of 15% formalin into a rear paw. Formalin injection produces continuous pain that results in two stereotypic behaviors, paw licking and paw lifting. Ten minutes after i.c.v, injection rats were observed for an 8 rain period and scored for formalin-induced behavior. All agonists produced analgesia as indicated by a dose-dependent attenuation of formalin-induced behavior. At the doses tested, the rank order of analgesic efficacy was DAGO > DPDPE > U50488H. We suggest that centrally located /~, 8 and x opioid receptors can each modulate the perception of this clinically relevant form of continuous pain. Additionally, the highest dose of DPDPE tested significantly increased rearing whereas DAGO and U50488H failed to affect rearing.
Pharmacology Biochemistry and Behavior, 1991
DALCE (1-40 micrograms, ICV), a short-acting agonist and long-acting antagonist at the delta opioid receptor, was examined for its effects upon food intake in rats under spontaneous, deprivation, glucoprivic and palatable conditions. DALCE (10 micrograms) significantly stimulated free feeding for up to 10 h but only minimally decreased (40 micrograms) food intake and body weight after 24-72 h. DALCE, administered prior to food deprivation (24 h), failed to affect subsequent 24-h intake and sporadically decreased intake and body weight change after 48-72 h. 2-Deoxy-D-glucose (650 mg/kg, IP) hyperphagia was transiently (2 h) decreased by long-term DALCE (10 micrograms) pretreatment. Hyperphagia following exposure to a high-fat diet was significantly potentiated by long-term DALCE (1 microgram) pretreatment. DALCE (10 micrograms) hyperphagia (2-10 h) was eliminated by central pretreatment with either naltrexone (20 micrograms) or the kappa antagonist, nor-binaltorphamine (20 micrograms) but was minimally affected by central pretreatment with the mu antagonist, beta-funaltrexamine (20 micrograms) or long-term DALCE (40 micrograms). The general inability of the antagonist actions of DALCE to alter these forms of feeding argues against a role for the delta opioid receptor in these responses.
Brain Research, 1985
D-Ala2-D-LeuS-enkephalin (DADL) along with dimers formed from tetra(DTE: des-LeuS-enkephalin)-or pentapeptide (DPE: LeuS-enkephalin) coupled by methylene bridges of various lengths (n) have been shown in in vitro systems to possess varying degrees of~/6-receptor selectivity. In the present studies we have systematically compared the intrathecal effect of these agents and morphine on the cutaneous stimuli (hot plate (HP) and tail flick (TF)) and visceral-chemical (writhing) tests in the rat. The following observations were made. (1) Dimers with high 6-receptor selectivity were active in the TF (DPE 2-> DADL-> DTE 2 > morphine > DPE12 >>> DTE12 = 0) and HP (DPE 2-> DTE 2-> DADL-> morphine > DPE12-> DTE12 > 0. To examine cross-tolerance, the intrathecal EDs0 for morphine, DPE and DADL were determined in rats rendered tolerant by subcutaneous morphine pellets. The TF EDs0 tolerant/TF EDs0 naive was 18.4, 5.4 and 1.3, respectively. The ratio of activity on the HP was 14.0, 4.7 and 2.2. (2) On the visceralchemical test, only morphine was active. The dimers or DADL in doses which totally blocked the TF or HP are at higher doses which were just below those producing motor dysfunction had no effect on the writhing response. (3) At high intrathecal doses (40 x TF EDs0), morphine produced a motor rigidity which blocked the placing and stepping reflex. In contrast, injection of DADL and the more active dimers resulted in a waxy flaccidity at doses around 15-60 times the TF EDs0. These observations together offer strong support for a functional separation of two classes of spinal receptors which modulate the animal's response to distinguishable noxious stimuli.
Journal of Medicinal Chemistry, 1992
The cyclic peptide [2,6-dimethyl-Tyr1,~Penz,~Pen6]enkephalin (2) was synthesized by solid-phase techniques and contains the optically pure unnatural amino acid 2,6-dimethyltyrosine (DMT) as a replacement for the Tyrl residue of [~P e n~p P e n~] e n k e p h a l i n (DPDPE, 1). This structural modification resulted in a 10-fold increase in the potency of 2 at the S opioid receptor and a 35-fold increase in potency at the p receptor while substantial S receptor selectivity was maintained. In addition, 2 was 86-fold more effective than 1 at inhibiting electrically stimulated contractions of the mouse vas deferens. In the hot plate test, 2 was 7-fold more potent than 1 after intracerebroventricular administration in the mouse. While 1 waa inactive following systemic administration of doses as high aa 30 mg/kg, subcutaneous administration of 2 significantly inhibited writhing with an EDw of 2.6 mg/kg. Thew resulfe demonstrate that the potency and systemic activity of DPDPE are significantly increased by replacement of Tyrl with DMT.
Pharmacology Biochemistry and Behavior, 1991
CALCAGNETrI, D. J. AND S. G. HOLTZMAN. Delta opioid antagonist, naltrindole, selectively blocks analgesia induced by DPDPE but not DAGO or morphine. PHARMACOL BIOCHEM BEHAV 38(1) 185-190, 1991.--Initial reports suggest that naltrindole hydrochloride (NTI), a recently developed opioid, acts as a selective delta (5) antagonist in vivo. Three experiments were conducted in rats to test NTI for its ability to dose-dependently and selectively block the analgesia produced by a 8-selective opioid agonist without affecting analgesia produced by mu (p.) receptor opioid agonists. Intracerebroventricular (ICV) administration of the 8-selective agohist, DPDPE (30 p.g/rat), and the p~-selective agonist, DAGO (0.3 p.g/rat), increased paw-lick latency (2-fold relative to baseline) in the hot-plate assay. NTI (0.01-1.0 p,g/rat, ICV) dose-dependendy attenuated DPDPF_,-induced analgesia (1.0 p,g reduced paw-lick latency to baseline), but failed to affect DAGO-induced analgesia at any dose tested. A third experiment determined whether the ICV administration of NTI (1.0 p.g/rat) would attenuate restraint stress-induced potentiation of morphine analgesia as indexed by the tail-flick assay. Rats that underwent 5 days of 1 h restraint stress and nonstressed rats were injected subcutaneously with morphine (1.0-8.0 mg/kg). The magnitude (>2-fold) and duration of morphine-induced analgesia in restrained rats were significantly potentiated compared to nonstressed rats. NTI (1 p.g, ICV) failed to affect the magnitude and duration of morphine-induced analgesia regardless of restraint treatment. Thus, NTI failed to attenuate the analgesia produced by DAGO or morphine (in two assays of antinoeiception), whereas NTI (0.01-1.0 p,g, ICV) antagonized dose-dependently DPDPE-induced analgesia. These results support the view that NTI is a selective 8-receptor antagonist in vivo.
Dalargin and [Cys-(O2NH2)]2 analogues of enkephalins and their selectivity for μ opioid receptors
General Pharmacology: The Vascular System, 1995
1. Effects of the enkephalins Met-enk (M) and Leu-enk (L), of two newly synthesized analogues--[Cys-(O2NH2)]2-Met-enk (CM) and [Cys-(O2NH2)]2-Leu-enk (CL)--and of a hexapeptide--D-Ala2-Leu5-Arg6 (Dalargin; DL) on the spontaneous and electrically stimulated activity were examined with respect to their selectivity for the mu opioid receptors in the longitudinal layer of guinea pig ileum. 2. M and CM exerted relaxing and contractile effects on the spontaneous contractile activity while L, CL and DL produced only relaxation. The order of potency towards the relaxatory phase was DL > M > CM > L > CL and towards the contractile phase CM > M. 3. The effects of enkephalins on the spontaneous activity were naloxone and TTX sensitive except for the contractile phase of M and CM which persisted in the presence of TTX. NO was not involved in the neurotransmission of the relaxatory responses, while the blockade of alpha and beta adrenoceptors showed the participation of adrenergic mechanisms. Relaxation and contraction induced by enkephalins could not be directly attributed to cholinergic neurotransmission. 4. The naloxone-sensitive and concentration-dependent inhibitory effects of enkephalins and their analogues on the electrically stimulated cholinergic contractions were established. The order of the relative potency of opioids was: DL-3.8; M-1.0; L-0.4; CM-0.01; CL-0.005. 5. These data indicated that the D-Ala2 substitution and lengthening of the peptide chain by Arg6 in the molecule of L increased the potency at the mu opiate receptors, while the substitution in position 2 with Cys-(O2NH2) in the molecule of M and L yielded a less potent and selective mu agonists.
Acta Neurobiologiae Experimentalis, 1999
Background and aims: We systematically characterized the potency and side effect profile of a series of small opioid peptides with high affinity for the mu opioid receptor. Methods: Male Sprague Dawley rats were prepared with intrathecal (IT) catheters, assessed with hind paw thermal escape and evaluated for side effects including Straub tail, truncal rigidity, and pinnae and corneal reflexes. In these studies, DMT-DALDA (dDAL) (H-Dmt-D-Arg-Phe-Lys-NH 2 MW = 981), dDALc (H-Dmt-Cit-Phe-Lys-NH 2 MW = 868), dDALcn (H-Dmt-D-Cit-Phe-Nle-NH 2 MW = 739), TAPP (H-Tyr-D-Ala-Phe-Phe-NH 2 MW = 659), dDAL-TICP ([Dmt1]DALDA-(CH 2) 2-NH-TICP[psi]; MW = 1519), and dDAL-TIPP (H-Dmt-D-Arg-Phe-Lys(N ε-TIPP)-NH 2 were examined. In separate studies, the effects of approximately equiactive doses of IT DMT DALDA (10 pmol), morphine (30 nmol) and fentanyl (1 nmol) were examined on formalin-induced flinching at different pretreatment intervals (15 min-24 h). Results: (1) All agents resulted in a dose-dependent reversible effect upon motor function (Straub Tail > Truncal rigidity). (2) The ordering of analgesic activity (%MPE) at the highest dose lacking reliable motor signs after bolus delivery was: DMT-DALDA (80% ± 6/3 pmol); dDALc (75% ± 8/1 pmol); dDALcn (84% ± 10/300 pmol); TAPP (56% ± 12/10 nmol); dDAL-TICP (52% ± 27/300 pmol). (3) All analgesic effects were reversed by systemic (IP) naloxone (1 mg/kg). Naltrindole (3 mg/kg, IP) had no significant effect upon the maximum usable peptide dose. (4) Tolerance and cross-tolerance development after 5 daily boluses of DMT-DALDA (3 pmol) and morphine (30 nmol) revealed that both agents displayed a progressive decline over 5 days. (5) Cross-tolerance assessed at day 5 revealed a reduction in response to morphine in DMT-DALDA treated animal but not DMT-DALDA in the morphine treated animal, indicating an asymmetric cross-tolerance. (6) IT DMT-DALDA, morphine and fentanyl resulted in significant reductions in phase 1 and phase 2 flinching. With a 15 min pretreatment all drugs resulted in comparable reductions in flinching. However, at 6 h, the reduction in flinching after DMT-DALDA and morphine were comparably reduced while fentanyl was not different from vehicle. All effects on flinching were lost by 24 h. Conclusions: These results emphasize the potent mu agonist properties of the DALDA peptidic structure series, their persistence similar to morphine and their propensity to produce tolerance. The asymmetric cross-tolerance between equiactive doses may reflect the relative intrinsic activity of morphine and DMT-DALDA. Implications: These results suggest that the DALDA peptides with their potency and duration of action after intrathecal delivery suggest their potential utility for their further development as a spinal therapeutic to manage pain.
Characterization of supraspinal antinociceptive actions of opiod delta agonists in the rat
Pain, 1995
Supraspinally mediated antinociception has been clearly established for agonists acting via both/~and 8-opioid receptors. The present experiments were undertaken to further characterize the role of supraspinal opioid 3 receptors in the mediation of antinociception in rats and to examine the possible role of putative 81-and 82-opioid receptors in the antinociceptive effect. Cannulae directed at the right lateral ventricle, the periaqueductal gray (PAG), or the medullary reticular formation (MRF) were implanted in adult male, Sprague-Dawley rats for the microinjection of [D-Ala2,Glu4]deltorphin (8 2 agonist), [D-Pen2,o-PenS]enkephalin (DPDPE, 81 agonist), [D-Ser2,LeuS,Thr6]enkephalin (DSLET, mixed 8//z agonist) or morphine (reference /z-opioid). Pretreatments (24 h prior to agonist microinjection) were made with the putative t~ 1 and 3 2 antagonists, [D-AlaE,LeuS,Cys6]enkephalin (DALCE) and [o-AlaE,Cys4]deltorphin (Cys-DELT) and antinociception was measured in the 55°C hot plate (HP) and 52°C and 55°C (low and high intensity) warm-water tail-flick (TF) tests. Data were converted to percent maximal possible effect (%MPE). Intracerebroventricular (i.c.v.) administration of DPDPE produced less than a 50% MPE in the HP test whereas [D-Ala2,Glua]deltorphin produced Cys-DELT sensitive antinociception of up to 92% MPE. Neither i.c.v, agonist was effective in the TF assays, and both agonists were without effect in the PAG. [o-Ala2,Glu4]deltorphin microinjected into the MRF produced Cys-DELT sensitive antinociception of 60 and 47% MPE in the HP and low-intensity TF tests, respectively, but was not effective in the 55°C TF test; DPDPE did not produce antinociception when microinjected at this site. Microinjection of DSLET in the MRF produced significant antinociception in all three assays. Morphine produced antinociception following i.c.v, administration or microinjection into the PAG in all tests. Microinjection of morphine into the MRF produced antinociception in the HP and 52°C, but not 55°C, TF tests. Morphine antinociception was not antagonized by either DALCE or Cys-DELT. These data demonstrate that supraspinal ~-opioid receptors can be activated to elicit antinociception in the rat and that opioid 82 receptors predominate in this effect. Further, these effects may occur predominately via inhibition of supraspinally organized behavior without activation of descending systems such as those mediating the TF response in the rat.
European Journal of Pharmacology, 1987
Jimpy (B6CBA-A W-J/A-Ta jp) mice, which are known to be deficient in neuronal cerebroside sulfate (a putative component of the/x opioid receptor), were non-responsive in the tail flick test (compared to littermate controls and a standard Swiss strain of mouse) to analgesic doses of two /t opioid receptor agonists, morphine sulfate and [D-Ala2,MePhe4,Gly-olS]enkephalin (DAGO). However, the jimpy mice responded normally (compared to controls) to the analgesic effects of the selective 8 opioid receptor agonist [D-P~n 5]enkephalin (DPLPE). These results suggest (1) that 8 opioid receptors can mediate analgesia and (2) that cerebroside sulfate is not necessary for 8 opioid receptor activation.