Photoactivatable Neuropeptides for Spatiotemporally Precise Delivery of Opioids in Neural Tissue

Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA.
Neuron (Impact Factor: 15.05). 01/2012; 73(2):249-59. DOI: 10.1016/j.neuron.2011.11.016
Source: PubMed


Neuropeptides activate G protein-coupled receptors to acutely modulate cellular excitability and synaptic transmission. However, due to the lack of reagents for precise delivery of peptides within dense brain tissue, the spatiotemporal scale over which neuropeptides act is unknown. To achieve rapid and spatially delimited delivery of neuropeptides in mammalian brain tissue, we developed photoactivatable analogs of two opioids: [Leu⁵]-enkephalin (LE) and the 8 amino acid form of Dynorphin A (Dyn-8). These peptides are functionally inactive prior to photolysis, and exposure to ultraviolet (UV) light causes clean release of LE and Dyn-8. Recordings from acute slices of rat locus coeruleus (LC) demonstrated that photorelease of LE activates mu opioid receptor-coupled K+ channels with kinetics that approach the limits imposed by G protein-mediated signaling. Temporally precise and spatially delimited photorelease revealed the kinetics and ionic nature of the mu opioid response and the mechanisms that determine the spatial profile of enkephalinergic volume transmission in LC.

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Available from: Matthew R Banghart, Apr 02, 2014
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    • "The use of photosensitive compounds that act as photo-switches or ligands that bind to channels or receptors upon photo-conversion (Kramer et al., 2013) could exploit the high spatiotemporal control of both fluid and light delivery afforded by these optofluidic probes. Optopharmacological agents have been enthusiastically received in neuroscience for in vitro applications (Banghart and Sabatini, 2012; Callaway and Katz, 1993; Carter and Sabatini, 2004; Matsuzaki et al., 2001), but their use in vivo has been limited. Although compelling findings exist addressing the external visual nervous system and the surface of the cortex (Mourot et al., 2012; Noguchi et al., 2011; Polosukhina et al., 2012; Tochitsky et al., 2014), optopharmacological application in the deep brain remains a significant challenge. "
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    Cell 07/2015; 162(3). DOI:10.1016/j.cell.2015.06.058 · 32.24 Impact Factor
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    • "The traditional view is that G protein-linked signaling is restricted to the plasma membrane and based on rapid diffusion of downstream mediators. However, it is increasingly clear that even classical ''diffusible'' mediators such as cAMP are spatially restricted through local synthesis and destruction (Willoughby et al., 2006), and neuromodulators such as opioid neuropeptides exhibit a limited range of action in neural tissue (Banghart and Sabatini, 2012). Accordingly, the precise subcellular location of 7TMR activation is likely to be an important parameter in neuromodulation, particularly for projection neurons and neurons with extensive dendritic arbors. "
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