Effects of dynorphin A(1-13) on opiate withdrawal in humans.

The objectives of the current study were to determine 1) the effects of various doses of dynorphin A (1-13) on opiate withdrawal in humans and 2) the safety of dynorphin at these doses. Opiate dependent subjects who had been stabilized on morphine received a single IV dose of placebo, 150, 500 or 1000 microg/kg dynorphin after exhibiting spontaneous withdrawal using a randomized, double-blinded, between-subjects study design. Observer Withdrawal Scores were lower in the 150 and 1000 microg/kg groups as compared to placebo (P < 0.05) but no significant differences were observed on the observer-rated Wang or Sickness Scales. Significant decreases were also found for self-reported symptoms of nervousness, runny nose, sneezing, and painful joints in the 500 microg/kg group. Significant increases in serum prolactin levels were seen after all dynorphin doses; however, these were not dose-related. Dynorphin A (1-13) was well tolerated and safe, with no changes in physiologic parameters. We conclude that dynorphin A (1-13) has a modest effect in reducing mild opiate withdrawal in humans and is well tolerated at doses up to 1000 microg/kg.

Effects of high intravenous doses of dynorphin A(1-13) on tail flick latency and central nervous system histology in rats.

Dynorphin A(1-13) blocks opiate withdrawal in rats without producing dependence, and enhances analgesia in morphine-tolerant animals. Its potential use in humans is therefore of interest. Dynorphin A(1-13) has little toxicity when administered at modest doses IV but has been reported to cause hindlimb paralysis and necrosis of the spinal cord in rats, at the catheter tip, when administered intrathecally. To further evaluate its potential neurotoxicity, we administered dynorphin A(1-13) to rats at very high doses IV. Rats (n = 6-10 per group) received dynorphin A(1-13) as bolus IV doses of 5 mg/kg, or as continuous IV infusions of 40 mg/kg/day for 1 day, with saline controls. The appearance and behavior of all animals was normal. Tail flick latencies remained unchanged (p > 0.5). There were no histologic abnormalities of the spinal cord or brain when examined by light microscopy. Two additional groups received bolus injections of dynorphin A(1-13) 50 or 100 mg/kg IV. Animals receiving 50 mg/kg showed cutaneous flushing, labored respirations, and decreased spontaneous movement, which resolved within 10 min. Histology at 1 week was normal. All six animals receiving 100 mg/kg convulsed and died within minutes. Three animals that received dynorphin A(1-13) 40 mg/kg/day for 7 days had normal behavior and histology. We conclude that the previously observed neurotoxicity of intrathecally administered dynorphin A(1-13) is a local effect that does not occur when dynorphin A(1-13) is administered IV, even at very high doses.

[Des-Tyr1]dynorphin A-(2-17) has naloxone-insensitive antinociceptive effect in the writhing assay.

The dynorphin family of peptides stands out among the opioids in that its members are not antinociceptive after central administration in the common antinociceptive assays. In addition, reports of spinal antinociception have been conflicting. We have tested the antinociceptive activity of i.v. dynorphin A-(1-13) in the writhing assay and have found it to be very potent, with an ED50 of 1.0 (0.99-1.02) mumol/kg. Remarkably, [des-tyr1]dyn A-(2-17) was equally active with an ED50 of 1.1 (0.99-1.20). This activity was also retained by several smaller, non-opioid dynorphin A fragments and was not affected by the presence of either 50 mumol/kg naloxone or 20 mumol/kg Nor-BNI. Further, ED50 values were not different in morphine-dependent mice. The peak effect of dyn A-(1-13) and A-(2-17) was observed 5 min after administration and the effect of dyn A-(1-13) or dyn A-(2-17) was still measurable 1 hr after i.v. administration with a 5- to 6-fold increase in ED50 at this time. The ED50 values after i.c.v. and i.t. administration of dyn A-(1-13) were similar to those reported previously. Dyn A(2-17) was also effective by these routes with ED50 values not significantly different from those of dyn A-(1-13). Both dyn A-(1-13) and A-(2-17) were also active when injected i.p., whereas ED50 values increased substantially after s.c. administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Dynorphin A modulates acute and chronic opioid effects.

A single dose of dynorphin A-(1-13) [dyn A(1-13)] is effective in suppressing the expression of opioid withdrawal and tolerance in morphine-dependent mice. In addition, this modulatory activity is retained by the corresponding non-opioid [des-Tyr1]-dynorphin A peptide [dynA(2-17)]. We have further investigated the non-opioid nature of this activity by comparing the efficacies of dyn A(1-13) and (2-17) under different experimental protocols with a variety of dosing regimens. The effect of dyn A(1-13) on withdrawal and tolerance expression was dose-dependent and could be enhanced by repeated dosing. Thus, the ED50 of naloxone to precipitate withdrawal jumping was increased 1.8-fold when morphine-dependent mice were treated with 4.2 mumol/kg dyn A(1-13) on the fourth day after pellet implantation and 2.4-fold on the sixth day with continued daily dyn A(1-13) treatment. The maximal effect was observed on day 6 when the ED50 of mice treated with 8.4 mumol/kg of dyn A(1-13) was increased nearly 6-fold over that of saline controls. Dyn A(2-17) proved to be nearly as effective as dyn A(1-13).