A comparison of the analgesic effects of H-Dmt-D-Arg-Phe-Lys-NH2, a synthetic opioid peptide, and morphine in experimental neuropathic pain

Abstract

H-Dmt-D-Arg-Phe-Lys-NH2 ([Dmt1]DALDA) is a synthetic tetrapeptide with extraordinary selectivity for the mu-opioid receptor and has unique characteristics. [Dmt1]DALDA appears to act predominantly in the spinal cord to produce analgesia while morphine, the prototypical mu-opioid agonist, acts both in the brain and the spinal cord (1). Furthermore, [Dmt1]DALDA inhibits norepinephrine re-uptake (2) and it is also a mitochondria-targeted antioxidant (3). With these characteristics, [Dmt1]DALDA may be more effective as an analgesic than morphine especially in the treatment of neuropathic pain. This study was designed to compare the effects of systemic [Dmt1]DALDA and morphine on experimental neuropathic pain in rats. Neuropathic pain in the right hind limb was produced by tight ligation of the L5 spinal nerve and was evaluated by thermal hyperalgesia using the Hargreaves paw withdrawal test. ED30 and ED90 doses of morphine and [Dmt1]DALDA were determined by dose-response assays in naïve rats and their effects on thermal hyperalgesia in neuropathic animals were compared. Both ED30 and ED90 doses of [Dmt1]DALDA were more effective in increasing paw withdrawal latencies in neuropathic rats as compared to ED30 and ED90 doses of morphine, respectively. The results suggest that [Dmt1]DALDA may be a promising opioid compound for the treatment of neuropathic pain. Supported in part by a Grant-in-aid for Cancer Research (Study Group on Palliative Care and Psycho-oncology in Cancer Treatment) from the Ministry of Health and Welfare, Japan (NS). (1. Shimoyama, Pharmacol, 2009; 2.Shimoyama, J Pharmacol Exp Ther, 2001; 3. Szeto and Schiller, Pharm Res, 2011.) H-Dmt-D-Arg-Phe-Lys-NH2 ([Dmt1]DALDA) is a synthetic tetrapeptide with extraordinary selectivity for the mu-opioid receptor and has unique characteristics. [Dmt1]DALDA appears to act predominantly in the spinal cord to produce analgesia while morphine, the prototypical mu-opioid agonist, acts both in the brain and the spinal cord (1). Furthermore, [Dmt1]DALDA inhibits norepinephrine re-uptake (2) and it is also a mitochondria-targeted antioxidant (3). With these characteristics, [Dmt1]DALDA may be more effective as an analgesic than morphine especially in the treatment of neuropathic pain. This study was designed to compare the effects of systemic [Dmt1]DALDA and morphine on experimental neuropathic pain in rats. Neuropathic pain in the right hind limb was produced by tight ligation of the L5 spinal nerve and was evaluated by thermal hyperalgesia using the Hargreaves paw withdrawal test. ED30 and ED90 doses of morphine and [Dmt1]DALDA were determined by dose-response assays in naïve rats and their effects on thermal hyperalgesia in neuropathic animals were compared. Both ED30 and ED90 doses of [Dmt1]DALDA were more effective in increasing paw withdrawal latencies in neuropathic rats as compared to ED30 and ED90 doses of morphine, respectively. The results suggest that [Dmt1]DALDA may be a promising opioid compound for the treatment of neuropathic pain. Supported in part by a Grant-in-aid for Cancer Research (Study Group on Palliative Care and Psycho-oncology in Cancer Treatment) from the Ministry of Health and Welfare, Japan (NS). (1. Shimoyama, Pharmacol, 2009; 2.Shimoyama, J Pharmacol Exp Ther, 2001; 3. Szeto and Schiller, Pharm Res, 2011.)