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

Abstract

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. 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. 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. 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.