Tolerance develops in spinal cord, but not in brain with chronic [Dmt<sup>1</sup>]DALDA treatment

Ben, Yong; Smith, Andrew P.; Schiller, Peter W.; Lee, Nancy M.

doi:10.1038/sj.bjp.0706007

Cited by 12 publications

(2 citation statements)

References 23 publications

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“…As previously reported (19,20), intrathecal DMT-DALDA resulted in tolerance and dependency. Interestingly, a 7-day exposure led to a loss of any analgesic activity as measured by thermal escape and by inhibition of formalin-evoked flinching.…”

Section: Tolerancesupporting

confidence: 78%

Characterization of Analgesic Actions of the Chronic Intrathecal Infusion of H-Dmt-D-Arg-Phe-Lys-NH2 in Rat

Kokubu

Eddinger

Yamaguchi

et al. 2019

Neuromodulation: Technology at the Neural Interface

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Objectives DMT‐DALDA (H‐Dmt‐D‐Arg‐Phe‐Lys‐NH2; Dmt = 2′,6′‐dimethyltyrosine) is a selective mu opioid agonist. We sought to characterize efficacy, tolerance, dependence and side‐effect profile when given by continuous intrathecal infusion. Materials and Methods Adult male Sprague Dawley rats were prepared with chronic intrathecal catheters and osmotic mini‐pumps to deliver vehicle (saline), DMT‐DALDA or morphine. Hind paw thermal escape latencies were assessed. In addition, effects upon intraplantar formalin‐evoked flinching and withdrawal after 14 days of infusion were examined. The flare response after intradermal delivery was examined in the canine model. Results 1) Intrathecal infusion of 0.3 to 30 pmol/μL/hour of DMT‐DALDA or 37.5 nmol/μL/hour of morphine more than 7 or 14 days resulted in a dose‐dependent increase in thermal escape latency. The maximum antinociceptive effect was observed between 1 and 4 days after start of infusion with preserved cornea, blink, placing and stepping. By days 12 to 14, response latencies were below baseline. 2) On days 2 to 4 of DMT‐DALDA infusion, the pan opioid receptor antagonist naloxone (Nx), but not the delta‐preferring antagonist naltrindole, antagonized the analgesic effects. 3) Assessment of formalin flinching on day 1 following IT DMT‐DALDA Infusion showed significant analgesia in phases 1 and 2. On day 6 of infusion there was minimal effect, while on day 13, there was an increase in flinching. 4) On days 7 and 14 of infusion Nx resulted in prominent withdrawal signs indicating dependence and withdrawal. 5) Intradermal morphine and DMT‐DALDA both yield a naltrexone‐insensitive, cromolyn‐sensitive flare in the canine model at similar concentrations. Conclusions These data suggest that DMT‐DALDA is a potent, spinally active agonist with a propensity to produce tolerance dependence and mast cell degranulation. While it was equiactive to morphine in producing mast cell degranulation, it was >1000 fold more potent in producing analgesia, suggesting a possible lower risk in producing a spinal mass at equianalgesic doses.

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Section: Tolerancesupporting

confidence: 78%

Characterization of Analgesic Actions of the Chronic Intrathecal Infusion of H-Dmt-D-Arg-Phe-Lys-NH2 in Rat

Kokubu

Eddinger

Yamaguchi

et al. 2019

Neuromodulation: Technology at the Neural Interface

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“…The only drawback of this compound is that it produced quite profound tolerance after chronic i.th. administration (Zhao et al 2002; Ben et al 2004). [Dmt 1 ]DALDA was also 100–200-fold more potent than morphine in the mouse tail-flick test when given by the intracerebroventricular (i.c.v.)…”

Section: [Dmt1]dalda: a Trifunctional Opioid Analgesicmentioning

confidence: 99%

Bi- or multifunctional opioid peptide drugs

2010

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Strategies for the design of bi-or multifunctional drugs are reviewed. A distinction is made between bifunctional drugs interacting in a monovalent fashion with two targets and ligands containing two distinct pharmacophores binding in a bivalent mode to the two binding sites in a receptor heterodimer. Arguments are presented to indicate that some of the so-called "bivalent" ligands reported in the literature are unlikely to simultaneously interact with two binding sites. Aspects related to the development of bi-or multifunctional drugs are illustrated with examples from the field of opioid analgesics. The drug-like properties of the tetrapeptide Dmt 1 [DALDA] with triple action as a μ opioid agonist, norepinephrine uptake inhibitor and releaser of endogenous opioid peptides to produce potent spinal analgesia are reviewed. Rationales for the development of opioid peptides with mixed agonist/antagonist profiles as analgesics with reduced side effects are presented. Progress in the development of mixed μ opioid agonist/δ opioid antagonists with low propensity to produce tolerance and physical dependence is reviewed. Efforts to develop bifunctional peptides containing a μ opioid agonist and a cholecystokinin antagonist or an NK1 receptor antagonist as analgesics expected to produce less tolerance and dependence are also reviewed. A strategy to improve the drug-like properties of bifunctional opioid peptide analgesics is presented.

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Opioid Peptide-Derived Analgesics

Schiller¹

2008

Drug Addiction

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A BSTRACTTwo recent developments of opioid peptide-based analgesics are reviewed. The fi rst part of the review discusses the dermorphin-derived, cationic-aromatic tetrapeptide H-Dmt-D-Arg-Phe-Lys-NH 2 ([Dmt 1 ]DALDA, where Dmt indicates 2 ′ ,6 ′ -dimethyltyrosine), which showed subnanomolar m receptor binding affi nity, extraordinary m receptor selectivity, and high m agonist potency in vitro. In vivo, [Dmt 1 ]DALDA looked promising as a spinal analgesic because of its extraordinary antinociceptive effect (3000 times more potent than morphine) in the mouse tail-fl ick assay, long duration of action (4 times longer than morphine), and lack of effect on respiration. Unexpectedly, [Dmt 1 ]DALDA also turned out to be a potent and long-acting analgesic in the tail-fl ick test when given subcutaneously (s.c.), indicating that it is capable of crossing the blood-brain barrier. Furthermore, little or no cross-tolerance was observed with s.c. [Dmt 1 ]DALDA in morphine-tolerant mice. The second part of the review concerns the development of mixed µ agonist/ d antagonists that, on the basis of much evidence, are expected to be analgesics with a low propensity to produce tolerance and physical dependence. The prototype pseudopeptide H-Dmt-Tic Y [CH 2 NH]PhePhe-NH 2 (DIPP-NH 2 [ Y ], where Tic indicates 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) showed subnanomolar m and d receptor binding affi nities and the desired m agonist/ d antagonist profi le in vitro. [ Y ] produced a potent analgesic effect after intracerebroventricular administration in the rat tail-fl ick assay, no physical dependence, and less tolerance than morphine. The results obtained with DIPP-NH 2 [ Y ] indicate that mixed m agonist/ d antagonists look promising as analgesic drug candidates, but compounds with this profi le that are systemically active still need to be developed. INTRODUCTIONThe clinical treatment of severe pain relies heavily upon opioid analgesics, most of which act via m opioid receptors.Morphine and other centrally acting m opioid analgesics produce, in addition to the analgesic effect, several side effects -including inhibition of gastrointestinal motility, respiratory depression, tolerance, and physical dependence -that limit their use in pain treatment. Kappa opioid agonists have also been shown to be potent analgesics; however, it has long been recognized that centrally acting k agonists have limited usefulness in humans because of their psychotomimetic and dysphoric effects. 1 , 2 Delta opioid agonists are known to produce analgesic effects when given intrathecally (i.th) 3 , 4 or intracerebroventricularly (i.c.v.). 4 There is evidence to indicate that they induce less tolerance and physical dependence than m analgesics, no respiratory depression, and few or no adverse gastrointestinal effects. [5][6][7] Among the peptide d opioid agonists, [D-Pen 2 , D-Pen 5 ]enkephalin (DPDPE) produced only a weak, centrally mediated analgesic effect after systemic administration, indicating that it does not cross the blood-brain barrie...

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

Cited by 12 publications

References 23 publications

Characterization of Analgesic Actions of the Chronic Intrathecal Infusion of H-Dmt-D-Arg-Phe-Lys-NH2 in Rat

Characterization of Analgesic Actions of the Chronic Intrathecal Infusion of H-Dmt-D-Arg-Phe-Lys-NH2 in Rat

Bi- or multifunctional opioid peptide drugs

Opioid Peptide-Derived Analgesics

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

Cited by 12 publications

References 23 publications

Characterization of Analgesic Actions of the Chronic Intrathecal Infusion of H-Dmt-D-Arg-Phe-Lys-NH2 in Rat

Characterization of Analgesic Actions of the Chronic Intrathecal Infusion of H-Dmt-D-Arg-Phe-Lys-NH2 in Rat

Bi- or multifunctional opioid peptide drugs

Opioid Peptide-Derived Analgesics

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