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

The opioid peptide dynorphin A is known to elicit a number of pathological effects that may result from neuronal excitotoxicity. An up-regulation of t his peptide has also been causally related to the dysesthesia associated wi th inflammation and nerve injury. These effects of dynorphin A are not medi ated through opioid receptor activation but can be effectively blocked by p retreatment with N-methyl-D-aspartate (NMDA) receptor antagonists, thus imp licating the excitatory amino acid system as a mediator of the actions of d ynorphin A and/or its fragments. A direct interaction between dynorphin A a nd the NMDA receptors has been well established; however the physiological relevance of this interaction remains equivocal. This study examined whethe r dynorphin A elicits a neuronal excitatory effect that may underlie its ac tivation of the NMDA receptors. Calcium imaging of individual cultured cort ical 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-resp onsive cells. Thus dynorphin A stimulates neuronal cells via a nonopioid, n on-NMDA mechanism. This excitatory action of dynorphin A could modulate NMD A receptor activity in vivo by enhancing excitatory neurotransmitter releas e or by potentiating NMDA receptor function in a calcium-dependent manner. Further characterization of this novel site of action of dynorphin A may pr ovide new insight into the underlying mechanisms of dynorphin excitotoxicit y and its pathological role in neuropathy.