Local inhibitory effects of dynorphin A-(1–17) on capsaicin-induced thermal allodynia in rhesus monkeys

Abstract

Although dynorphin A-(1-17) has been characterized in vitro as a high efficacy kappa-opioid receptor agonist, functional studies of dynorphin A-(1-17) following central or systemic administration indicate the involvement of both opioid and non-opioid components. The aim of this study was to investigate whether local administration of dynorphin-related analogs can attenuate capsaicin (8-methyl-N-vanillyl-6-nonenamide)-induced nociception and what type of opioid receptor mediates the local action of dynorphin A-(1-17) in monkeys. Capsaicin (100 microg) was used to evoke a nociceptive response, thermal allodynia, which was manifested as a reduced tail-withdrawal latency in normally innocuous 46 degrees C warm water. Co-administration of dynorphin A-(1-17) (0.3-10 microg) with capsaicin in the tail dose-dependently inhibited thermal allodynia; however, both non-opioid fragments dynorphin A-(2-17) (10-300 microg) and dynorphin A-(2-13) (10-300 microg) were ineffective. Local antiallodynia of dynorphin A-(1-17) was antagonized by a small dose (100 microg) of an opioid receptor antagonist, quadazocine, applied s.c. in the tail. Pretreatment with a selective kappa-opioid receptor antagonist, nor-binaltorphimine (nor-BNI), s.c. 320 microg in the tail also reversed local antiallodynia of dynorphin A-(1-17). Both locally effective doses of antagonists, when applied s.c. in the back, did not antagonize local dynorphin A-(1-17), indicating that peripheral kappa-opioid receptors selectively mediated the local action of dynorphin A-(1-17) in the tail. In addition, a much larger dose of dynorphin A-(1-17) (1000 microg), when administered s. c. in the back or i.m. in the thigh, did not cause sedative or diuretic effects. These results suggest that in vivo opioid actions of dynorphin-related peptides can be differentiated locally in this procedure. They also indicate that local application of peptidic ligands may be a useful medication for localized pain.

[Nα-BenzylTyr,cyclo(d-Asp5,Dap8)]- dynorphin A-(1−11)NH2Cyclized in the “Address” Domain Is a Novel κ-Opioid Receptor Antagonist

“…The decrease in affinity was particularly striking for the cyclic peptide 2 at µ-opioid receptors, resulting in exceptional selectivity (194-fold) for κ-over µ-opioid receptors. The low µ-opioid receptor affinity of 2 is a result of combining the N R -benzylTyr 1 modification with the [5,8] cyclization; the cyclic peptide cyclo[D-Asp 5 ,Dap 8 ]Dyn A-(1-13)-NH 2 without the N-terminal modification has much higher µ-opioid receptor affinity (K i ) 75 nM) than 2 and only modest selectivity (9-fold) for κ-over µ-opioid receptors. 29 The C-terminal domain of the peptides has a marked effect on the efficacy observed in the adenylyl cyclase assay using CHO cells stably expressing κ-opioid receptors.…”

The efficacy of Dynorphin fragments at the κ, μ and δ opioid receptor in transfected HEK cells and in an animal model of unilateral peripheral inflammation

“…Our results showed limited biotransformation of the peptides occurred over the 30 min period in the assay. While this biotransformation occurred, for no peptides did the concentration decrease by more than 45% and with one peptide (dynorphin [1][2][3][4][5][6] showing no detectable degradation. This level of degradation is unlikely to have a significant effect on the IC50 of the peptides observed.…”

“…Dynorphins are a series of peptides that bind to the κ-opioid receptor (KOP) and mediate anti-nociception peripherally [1,2]. In the periphery, leukocytes have been shown to invade sites of inflammation and release opioid peptides including dynorphin A 1-17, in response to pro-inflammatory interleukin-1β and lipopolysaccharide [3][4][5].…”

“…The administration of dynorphin 1-17 has been shown to reduce peripheral hyperalgesia in a range of animal models of pain [1,2]. The dynorphin fragments produced in the biotransformation study were produced in an inflamed tissue homogenate, leaving the question of the role these dynorphin fragments play in inflammatory pain unanswered.…”

Synthesis of novel basic head‐to‐side‐chain cyclic dynorphin A analogs: Strategies and side reactions

“…2 Besides their role in analgesia, [2][3][4][5][6][7] -opioid receptor agonists may also have other therapeutic applications, including in the treatment of cocaine dependence, 8 -10 as neuroprotective and anticonvulsant agents, 11 and for the treatment of HIV-1 and HIV-1 related encephalopathy.…”