Stabilized dynorphin derivatives for modulating antinociceptive activity in morphine tolerant rats: Effect of different routes of administration

Abstract

Dynorphins, such as dynorphin A(1-13) (Dyn A(1-13)), have been shown to enhance analgesia in morphine-tolerant animals, despite their very short half-life after intravenous administration. The potential use of dynorphins in humans is therefore of interest. This laboratory has recently evaluated the metabolic fate of stabilized dynorphin derivatives. This study was conducted to evaluate whether such stabilized derivatives, ie, [NMet-Tyr 1 ]-Dynorphin A(1-13) (N-MT Dyn A, stabilized at the N-terminal end) and [N-Met-Tyr 1 ]-Dynorphin A(1-13) amide (N-MT Dyn A amide, stabilized at the C-and N-terminal ends), would enhance the antinociceptive activity of morphine not only after intravenous administration but also after subcutaneous and pulmonary delivery. Intravenous administration of N-MT Dyn A (5 µmol/kg) and N-MT Dyn A amide (5 µmol/kg) to morphine-tolerant rats resulted in significantly higher tail-flick latencies than those observed for the saline group. These effects could be observed for up to 2.0 ± 0.1 hours after intravenous administration of N-MT Dyn A and for up to 3.4 ± 1.4 hours for N-MT Dyn A amide. The time-averaged effects of both peptides were similar. After pulmonary delivery of the same dose, derivatives remained active. The duration of the effects after pulmonary administration of the amide was 4.4 ± 2.5 hours while that of N-MT Dyn A was slightly shorter (2.8 ± 0.9 hours). No effect was observed after subcutaneous administration of N-MT Dyn A. These results suggest that pulmonary delivery of stabilized dynorphin derivatives represents a possible alternative to intravenous administration.

Opioid peptides: potential for drug development

“…in structural modification strategies, pulmonary delivery [23] and demonstrated activity following oral administration, hold promise that opioid peptides can be systemically administered by a variety of methods including those that don’t involve injection to yield therapeutic benefit.…”

“…Like the parent peptide, these analogs did not produce antinociceptive tolerance. [NMeTyr 1 ]dynorphin A-(1-13) and its C-terminal amide derivative have been shown to enhance morphine-induced antinociception in morphine-tolerant rats after systemic administration [23]. Interestingly, although the compounds were not active after s.c. administration, they were active following pulmonary delivery.…”

“…The demonstration of oral activity at reasonable doses for some opioid peptides suggests the possibility in selected cases to develop orally active opioid peptides, but it will be necessary to explore other routes of administration for a number of therapeutically relevant peptides. The demonstrated activity of dynorphin analogs following inhalation [23] suggest that it may be possible to administer these peptides by other methods not involving injection that could increase acceptance of such therapeutic agents.…”

Zyklophin, a systemically active selective kappa opioid receptor peptide antagonist with short duration of action

“…While the delivery of peptides as therapeutic agents remains a challenge, the development of alternatives to injection for systemic administration will facilitate their clinical use. The recent demonstration of the activity of Dyn A-(1-13) analogs following inhalation (38) shows that other routes of administration can be used for opioid peptides that could increase their acceptance as therapeutic agents.…”

Reinstatement of cocaine place-conditioning prevented by the peptide kappa-opioid receptor antagonist arodyn

“…While the present study has utilized i.c.v. administration of arodyn, a number of studies have shown that dynorphin A analogs can cross the blood-brain barrier and remain active after systemic administration (Yu et al, 1997;Butelman et al, 1999;Hiramatsu et al, 2001;Brugos et al, 2004). In recent work, arodyn has been shown to cross a model of the blood-brain barrier (Chappa, Fang, Aldrich and Lunte, manuscript in preparation).…”