Central and peripheral actions of the novel κ‐opioid receptor agonist, EMD 60400

Barber, Andrew; Bartoszyk, Gerd D.; Greiner, Hartmut E.; Mauler, Frank; Murray, Robert; Seyfried, Christoph A.; Simon, Maxime; Gottschlich, Rudolf; Harting, J.; Lues, Inge

doi:10.1111/j.1476-5381.1994.tb14815.x

Cited by 23 publications

(29 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, previous studies found that structurally related tetrapeptides also functioned as peripherally restricted agonists (Dooley et al, 1998;Vanderah et al, 2004Vanderah et al, , 2008. ICI204448 is a nonpeptidic small molecule that has also been described as a peripherally restricted -selective agonist (Shaw et al, 1989), and previous studies have reported dose-dependent and receptormediated antinociceptive effects in various assays of painstimulated behavior, including assays of acid-stimulated stretching in mice and rats (Barber et al, 1994;Keïta et al, 1995;Caram-Salas et al, 2007). Results of the present study are consistent with this characterization insofar as ICI204448, like ffir, produced dose-dependent antinociception in the assay of acid-stimulated stretching at doses that did not decrease ICSS in the absence of a noxious stimulus.…”

Section: Discussionmentioning

confidence: 99%

“…; 30 min), ICI204448 (10 -32 mg/kg; 30 min), ketoprofen (1 mg/kg; 30 min), cocaine (1-10 mg/kg; 10 min), and flupenthixol (0.1-1.0 mg/kg; 60 min). Doses and pretreatment times were based on preliminary studies and previous studies in the literature (Corbett, 1990;Barber et al, 1994;McCurdy et al, 2006;Chartoff et al, 2008;Spofford et al, 2009). Three sequential test components were conducted immediately after administration of lactic acid or its vehicle.…”

Section: Assay Of Intracranial Self-stimulationmentioning

confidence: 99%

“…However, peripherally restricted agonists such as the nonpeptide small molecule ((R,S)-N-[2-(Nmethyl-3,4-dichlorophenylacetamido)-2-(3-carboxyphenyl)-ethyl]pyrrolidine hydrochloride (ICI204448) and the tetrapeptide D-Phe-D-Phe-D-NIe-D-Arg-NH 2 [a.k.a. ff(D-Nle)r; FE200041] produced antinociception in the same assays at doses Ͼ20-fold lower than doses that produced signs of motor impairment (Barber et al, 1994;Vanderah et al, 2004). The clinical significance of these findings is a topic of active investigation (Machelska et al, 1999;Arendt-Nielsen et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Effects of Peripherally Restricted κ Opioid Receptor Agonists on Pain-Related Stimulation and Depression of Behavior in Rats

Negus¹,

O'Connell²,

Morrissey³

et al. 2011

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Opioid receptor agonists that do not readily cross the bloodbrain barrier are peripherally restricted and distribute poorly to the central nervous system after systemic administration. Peripherally restricted agonists have promise as candidate analgesics, because they may produce antinociception mediated by peripheral receptors more potently than they produce undesirable sedative and psychotomimetic effects mediated by central receptors. The present study used assays of painrelated stimulation and depression of behavior in rats to compare effects of 1) two peripherally restricted agonists [the, 2) a centrally penetrating agonist (salvinorin A), and 3) several reference drugs, including a nonsteroidal antiinflammatory drug (NSAID; ketoprofen). Intraperitoneal injection of dilute lactic acid served as a noxious stimulus to stimulate a stretching response and depress intracranial self-stimulation (ICSS) maintained by the delivery of electrical brain stimulation to the medial forebrain bundle. Acid-stimulated stretching was blocked by ketoprofen, the peripherally restricted agonists, and salvinorin A. However, acid-induced depression of ICSS was blocked only by ketoprofen. The peripherally restricted agonists had little effect, and salvinorin A exacerbated acidinduced depression of ICSS. These results suggest that peripherally restricted agonists may be safer than centrally penetrating agonists but less efficacious than NSAIDS or opioid receptor agonists to block pain-related depression of behavior; however, the peripheral selectivity of ffir and ICI204448 is limited, and future studies with agonists capable of greater peripheral selectivity are warranted.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Assay Of Intracranial Self-stimulationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Effects of Peripherally Restricted κ Opioid Receptor Agonists on Pain-Related Stimulation and Depression of Behavior in Rats

Negus¹,

O'Connell²,

Morrissey³

et al. 2011

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…ICI 204,448 is approximately equipotent to EKC in peripheral tissue (Barber et al, 1994;Hunter et al, 1990), but is over 150 time less potent than EKC in behavioral measures that should involve central control (Carey and Bergman, 2001). ICI 204,448 significantly increased heart rate in squirrel monkeys and was only slightly less potent than EKC.…”

Section: Discussionmentioning

confidence: 99%

Effects of kappa opioid agonists alone and in combination with cocaine on heart rate and blood pressure in conscious squirrel monkeys

Schindler¹,

Graczyk²,

Gilman³

et al. 2007

European Journal of Pharmacology

View full text Add to dashboard Cite

As kappa agonists have been proposed as treatments for cocaine abuse, the cardiovascular effects of the kappa opioid receptor agonists ethylketocyclazocine (EKC) and enadoline were investigated in conscious squirrel monkeys. Both EKC and enadoline increased heart rate with little effect on blood pressure. This effect appeared to be specific for kappa receptors as the mu opioid agonist morphine did not mimic the effects of the kappa agonists. The opioid antagonist naltrexone, at a dose of 1.0 mg/kg, blocked the effect of EKC. An action at both central and peripheral receptors may be responsible for the heart rate increase following kappa agonist treatment. The ganglionic blocker chlorisondamine partially antagonized the effect of EKC on heart rate, suggesting central involvement, while the peripherally-acting agonist ICI 204,448 ((±)-1-[2,3-(Dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol hydrochloride) also increased heart rate, supporting a peripheral site of action. When given in combination with cocaine, EKC produced effects that were sub-additive, suggesting that the kappa agonists may be used safely as cocaine abuse treatments.

show abstract

“…The presence of the KOR in skin has previously been inferred from pharmacological studies involving local delivery of antagonists [32,33], but its cellular location has yet to be described. Exploiting the presence of KOR in the footpad skin and the increased levels in peripheral nerves, we tested the ability of asimadoline, a peripheral-acting selective KOR agonist [34,35], to alleviate sensory dysfunction induced by diabetes. Established tactile allodynia in diabetic rats was dose-dependently ameliorated by systemic delivery of asimadoline with an efficacy profile similar to that of morphine and gabapentin.…”

Section: Discussionmentioning

confidence: 99%

Dynorphin A, kappa opioid receptors and the antinociceptive efficacy of asimadoline in streptozotocin-induced diabetic rats

et al. 2006

View full text Add to dashboard Cite

Aims/hypothesis We investigated spinal and peripheral kappa opioid systems in diabetic rats. Materials and methods Dynorphin A, N-methyl-D-aspartate (NMDA) and kappa opioid receptor (KOR) were measured in spinal cord, dorsal root ganglia, peripheral nerves and foot skin of control and streptozotocin-induced diabetic rats by immunoassay and Western blotting. Behavioural assessments of paw tactile sensitivity and formalin-evoked hyperalgesia were performed in normal and diabetic rats before and after treatment with asimadoline. Results Dynorphin A protein levels were significantly increased in peripheral nerves and footpad skin of diabetic rats. Dynorphin A exhibits both anti-and pro-nociceptive properties depending on activation of either KOR or NMDA receptors. Spinal protein levels of these receptors were not changed by diabetes, while KOR levels in the sciatic and peroneal nerves were significantly increased. Exploiting the presence and elevated levels of KOR in the periphery, we investigated the effect of the peripheral KOR agonist asimadoline on formalin-evoked hyperalgesia and tactile allodynia in diabetic rats. Both formalin-evoked hyperalgesia and tactile allodynia in diabetic rats were acutely ameliorated by asimadoline. To confirm that the effect of asimadoline was related to its property as KOR agonist, diabetic rats were pretreated with the selective KOR antagonist nor-binaltorphimine. Intraplantar norbinaltorphimine abolished the ability of asimadoline to alleviate tactile allodynia in diabetic rats. Systemic and intrathecal nor-binaltorphimine partially inhibited the effect of asimadoline against formalin-evoked hyperalgesia in diabetic rats. Conclusions/interpretation Using selective peripheral KOR agonists to take advantage of elevated peripheral KOR expression may provide a novel therapeutic approach for painful diabetic neuropathy.

show abstract

Central and peripheral actions of the novel κ‐opioid receptor agonist, EMD 60400

Cited by 23 publications

References 22 publications

Effects of Peripherally Restricted κ Opioid Receptor Agonists on Pain-Related Stimulation and Depression of Behavior in Rats

Effects of Peripherally Restricted κ Opioid Receptor Agonists on Pain-Related Stimulation and Depression of Behavior in Rats

Effects of kappa opioid agonists alone and in combination with cocaine on heart rate and blood pressure in conscious squirrel monkeys

Dynorphin A, kappa opioid receptors and the antinociceptive efficacy of asimadoline in streptozotocin-induced diabetic rats

Contact Info

Product

Resources

About