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Endogenous opioid peptides have been linked to numerous physiological functions, including pain perception and the motivational drive associated with substance use disorders, but many fundamental aspects of transmission remain ambiguous. The kinetics of endogenous opioid peptides are thought to be slower and to last longer than those of more classical small-molecule neurotransmitters, like dopamine; however, a direct comparison of the release and diffusive spread of these molecules in the brain is lacking. Here, fast-scan cyclic voltammetry was coupled with carbon microelectrodes for co-detection of dopamine and met-enkephalin at single recording sites in rat striatal slices. The measurements used a voltammetric waveform that was specifically designed to minimize sensitivity to dopamine, maximize sensitivity to enkephalin, and minimize biofouling. Both neurotransmitter (dopamine) and neuropeptide (met-enkephalin, M-ENK) release scaled with stimulation duration. Interestingly, ENK dynamics in striatum displayed a unique biphasic profile with a significant latency to peak that occurred ∼30 s after stimulation, suggesting a sphere of influence that was ∼3x larger than that of dopamine. Mathematical modeling of the evoked M-ENK concentration profile suggests that multiple forms of ENK were released at once, such that some of the five-amino-acid form of M-ENK was released in exocytosis, and some was generated in the extracellular space by enzymatic cleavage of a larger form of ENK. Finally, a series of experiments combined solid-phase extraction with liquid-chromatography mass spectrometry to independently verify ENK release. The findings provide direct evidence to support widely held assumptions regarding neuropeptide release, and they demonstrate how different classes of signaling molecules can potentially affect distinct cellular populations in striatum─even when released at the same site.
Berger et al. (Sat,) studied this question.