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Neuromodulation. 2019 Feb 22. doi: 10.1111/ner.12925. [Epub ahead of print]

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

Author information

1
Department of Anesthesiology, University of California San Diego, La Jolla, CA, USA.
2
Department of Anesthesiology, Dokkyo Medical University, Tochigi, Japan.
3
Université de Strasbourg, Strasbourg, France.
4
Universidad Autónoma de Nuevo León, San Nicolás de los Garza, Nuevo Leon, Mexico.
5
Department of Pharmacology and Physiology, University of Montreal, Montreal, Quebec, Canada.
6
Montreal Clinical Research Institute, Montreal, Quebec, Canada.

Abstract

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.

KEYWORDS:

DMT1-DALDA; Dependence; formalin flinching; intrathecal infusion; mu opioid receptor; tolerance; withdrawal

PMID:
30794333
DOI:
10.1111/ner.12925

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