Dynorphin A elicits an increase in intracellular calcium in cultured neurons via a non-opioid, non-NMDA mechanism

Qingbo Tang, Ronald M. Lynch, Frank Porreca, Josephine Lai

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Abstract

The opioid peptide dynorphin A is known to elicit a number of pathological effects that may result from neuronal excitotoxicity. An up- regulation of this peptide has also been causally related to the dysesthesia associated with inflammation and nerve injury. These effects of dynorphin A are not mediated through opioid receptor activation but can be effectively blocked by pretreatment with N-methyl-D-aspartate (NMDA) receptor antagonists, thus implicating the excitatory amino acid system as a mediator of the actions of dynorphin A and/or its fragments. A direct interaction between dynorphin A and the NMDA receptors has been well established; however the physiological relevance of this interaction remains equivocal. This study examined whether dynorphin A elicits a neuronal excitatory effect that may underlie its activation of the NMDA receptors. Calcium imaging of individual cultured cortical neurons showed that the nonopioid peptide dynorphin A(2-17) induced a time- and dose-dependent increase in intracellular calcium. This excitatory effect of dynorphin A(2-17) was insensitive to (+)- 5-methyl- 10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine (MK-801) pretreatment in NMDA-responsive cells. Thus dynorphin A stimulates neuronal cells via a nonopioid, non-NMDA mechanism. This excitatory action of dynorphin A could modulate NMDA receptor activity in vivo by enhancing excitatory neurotransmitter release or by potentiating NMDA receptor function in a calcium-dependent manner. Further characterization of this novel site of action of dynorphin A may provide new insight into the underlying mechanisms of dynorphin excitotoxicity and its pathological role in neuropathy.

Original languageEnglish (US)
Pages (from-to)2610-2615
Number of pages6
JournalJournal of neurophysiology
Volume83
Issue number5
StatePublished - Jun 8 2000

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ASJC Scopus subject areas

  • Neuroscience(all)
  • Physiology

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