Kappa-Opioid Receptor Selectivity for Ischemic Neuroprotection with BRL 52537 in Rats

Zhizheng Zhang, Tsung Ying Chen, Jeffrey R. Kirsch, Thomas J K Toung, Richard J. Traystman, Raymond C. Koehler, Patricia D. Hurn, Anish Bhardwaj

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

κ-Opioid receptors (KOR) have been implicated in neuroprotection from ischemic neuronal injury, but less work has been performed with transient focal cerebral ischemia to determine the role of KOR during reperfusion. We tested the effects of a selective and specific KOR agonist, BRL 52537 hydrochloride [(± )-1-(3,4-dichlorophenyl)acetyl-2-(1-pyrrolidinyl)methylpiperidine], and the standard KOR antagonist, nor-binaltorphimine dihydrochloride [nor-BNI; 17,17′-(dicyclopropylmethyl)-6,6′,7,7′-6,6′-imino-7, 7′-binorphinan-3,4′,14,14′tetrol], on functional and histological outcome after transient focal ischemia in the rat. By use of the intraluminal filament technique, halothane-anesthetized adult male Wistar rats were subjected to 2 h of middle cerebral artery occlusion confirmed by laser Doppler flowmetry. In a blinded, randomized fashion, rats were treated with 1) saline (vehicle) 15 min before reperfusion followed by saline at reperfusion for 22 h, 2) saline 15 min before reperfusion followed by BRL 52537 (1 mg · kg-1 · h-1) at reperfusion for 22 h, 3) saline 15 min before reperfusion followed by nor-BNI (1 mg · kg -1 · h-1) at reperfusion for 22 h, or 4) nor-BNI (1 mg/kg) 15 min before reperfusion followed by BRL 52537 (1 mg · kg -1 · h-1) and nor-BNI (1 mg · kg -1 · h-1) at reperfusion for 22 h. Infarct volume (percentage of ipsilateral structure) analyzed at 4 days of reperfusion was significantly attenuated in saline/BRL 52537 rats (n = 8; cortex, 10.2% ± 4.3%; caudoputamen [CP], 23.8% ± 6.7%) (mean ± SEM) compared with saline/saline treatment (n = 8; cortex, 28.6% ± 4.9%; CP, 53.3% ± 5.8%). Addition of the specific KOR antagonist nor-BNI to BRL 52537 completely prevented the neuroprotection (n = 7; cortex, 28.6% ± 5.3%; CP, 40.9% ± 6.2%) conferred by BRL 52537. BRL 52537 did not produce postischemic hypothermia. These data demonstrate that KORs may provide a therapeutic target during early reperfusion after ischemic stroke.

Original languageEnglish (US)
Pages (from-to)1776-1783
Number of pages8
JournalAnesthesia and Analgesia
Volume97
Issue number6
StatePublished - Dec 2003
Externally publishedYes

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kappa Opioid Receptor
Reperfusion
Neuroprotection
1-(3,4-dichlorophenyl)acetyl-2-(1-pyrrolidinyl)methylpiperidine
Laser-Doppler Flowmetry
Middle Cerebral Artery Infarction
Transient Ischemic Attack
Opioid Receptors
Halothane
Hypothermia
norbinaltorphimine
Wistar Rats
Ischemia
Stroke

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine

Cite this

Zhang, Z., Chen, T. Y., Kirsch, J. R., Toung, T. J. K., Traystman, R. J., Koehler, R. C., ... Bhardwaj, A. (2003). Kappa-Opioid Receptor Selectivity for Ischemic Neuroprotection with BRL 52537 in Rats. Anesthesia and Analgesia, 97(6), 1776-1783.

Kappa-Opioid Receptor Selectivity for Ischemic Neuroprotection with BRL 52537 in Rats. / Zhang, Zhizheng; Chen, Tsung Ying; Kirsch, Jeffrey R.; Toung, Thomas J K; Traystman, Richard J.; Koehler, Raymond C.; Hurn, Patricia D.; Bhardwaj, Anish.

In: Anesthesia and Analgesia, Vol. 97, No. 6, 12.2003, p. 1776-1783.

Research output: Contribution to journalArticle

Zhang, Z, Chen, TY, Kirsch, JR, Toung, TJK, Traystman, RJ, Koehler, RC, Hurn, PD & Bhardwaj, A 2003, 'Kappa-Opioid Receptor Selectivity for Ischemic Neuroprotection with BRL 52537 in Rats', Anesthesia and Analgesia, vol. 97, no. 6, pp. 1776-1783.
Zhang Z, Chen TY, Kirsch JR, Toung TJK, Traystman RJ, Koehler RC et al. Kappa-Opioid Receptor Selectivity for Ischemic Neuroprotection with BRL 52537 in Rats. Anesthesia and Analgesia. 2003 Dec;97(6):1776-1783.
Zhang, Zhizheng ; Chen, Tsung Ying ; Kirsch, Jeffrey R. ; Toung, Thomas J K ; Traystman, Richard J. ; Koehler, Raymond C. ; Hurn, Patricia D. ; Bhardwaj, Anish. / Kappa-Opioid Receptor Selectivity for Ischemic Neuroprotection with BRL 52537 in Rats. In: Anesthesia and Analgesia. 2003 ; Vol. 97, No. 6. pp. 1776-1783.
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