Spatiotemporal Control of Opioid Signaling and Behavior

Siuda, Edward R.; Copits, Bryan A.; Schmidt, Martin; Baird, Madison A.; Al‐Hasani, Ream; Planer, William; Funderburk, Samuel C; McCall, Jordan G.; Gereau, Robert W.; Bruchas, Michael R.

doi:10.1016/j.neuron.2015.03.066

Cited by 127 publications

(125 citation statements)

References 42 publications

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“…This can now be achieved using these multichannel platforms to stimulate, inhibit, or modulate multiple circuits in the brain simultaneously while recording behavioral responses without the encumbrance of tethered wires. When combined with recently developed light-sensitive proteins for advanced types of in vivo optogenetics and behavioral experiments (3), such integration can provide clearer evidence for integrated function of targeted neural circuits in a host of animals via stimulation and/or inhibition of circuits or even signaling pathways (31).…”

Section: Discussionmentioning

confidence: 99%

Stretchable multichannel antennas in soft wireless optoelectronic implants for optogenetics

Park

Shin

McCall

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Optogenetic methods to modulate cells and signaling pathways via targeted expression and activation of light-sensitive proteins have greatly accelerated the process of mapping complex neural circuits and defining their roles in physiological and pathological contexts. Recently demonstrated technologies based on injectable, microscale inorganic light-emitting diodes (μ-ILEDs) with wireless control and power delivery strategies offer important functionality in such experiments, by eliminating the external tethers associated with traditional fiber optic approaches. Existing wireless μ-ILED embodiments allow, however, illumination only at a single targeted region of the brain with a single optical wavelength and over spatial ranges of operation that are constrained by the radio frequency power transmission hardware. Here we report stretchable, multiresonance antennas and battery-free schemes for multichannel wireless operation of independently addressable, multicolor μ-ILEDs with fully implantable, miniaturized platforms. This advance, as demonstrated through in vitro and in vivo studies using thin, mechanically soft systems that separately control as many as three different μ-ILEDs, relies on specially designed stretchable antennas in which parallel capacitive coupling circuits yield several independent, well-separated operating frequencies, as verified through experimental and modeling results. When used in combination with active motion-tracking antenna arrays, these devices enable multichannel optogenetic research on complex behavioral responses in groups of animals over large areas at low levels of radio frequency power (<1 W). Studies of the regions of the brain that are involved in sleep arousal (locus coeruleus) and preference/aversion (nucleus accumbens) demonstrate the unique capabilities of these technologies.wireless optogenetics | stretchable electronics | wireless power transmission | deep brain stimulation | antenna O ptogenetics exploits a toolbox of light-sensitive proteins for optical manipulation of neural networks as a powerful means for the study of circuit-level mechanisms that underlie psychiatric diseases (1-4). Canonical optogenetic experiments in the brain require cranial insertion of an optical fiber to illuminate a region of interest (5, 6). Although this approach permits simple behavior modeling, constraints in animal motion and alterations in natural behaviors due to fiber tethering and external fixation complicate use in chronic longitudinal models and in experiments that assess complex responses. Many of these limitations can be bypassed with optoelectronic technologies and wireless receivers, as recently demonstrated in optogenetic stimulation of the brain, the peripheral nerves, and the spinal cord (4, 7-13). Systems that offer soft, compliant mechanical properties and thin, fully implantable designs are particularly advantageous (7). These systems, however, have still not been optimized to fully take advantage of the power of combining mouse genetics/optogentics with long-term beha...

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Section: Discussionmentioning

confidence: 99%

Stretchable multichannel antennas in soft wireless optoelectronic implants for optogenetics

Park

Shin

McCall

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

117

101

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“…Furthermore, conditional knockout lines for both the NOP receptor and ppN/OFQ are in the final stages of development. These new mouse tools will allow for cell-type specific control as has just recently been reported for mu and kappa opioid systems (via optogenetics and chemogenetics) Siuda et al, 2015;Vardy et al, 2015) along with cell type-selective deletion studies to more mechanistically dissect N/OFQ and NOP receptor neural circuits that mediate behavior. 2.…”

Section: Future Directions and New Toolsmentioning

confidence: 99%

Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems

et al. 2016

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The NOP receptor (nociceptin/orphanin FQ opioid peptide receptor) is the most recently discovered member of the opioid receptor family and, together with its endogenous ligand, N/OFQ, make up the fourth members of the opioid receptor and opioid peptide family. Because of its more recent discovery, an understanding of the cellular and behavioral actions induced by NOP receptor activation are less well developed than for the other members of the opioid receptor family. All of these factors are important because NOP receptor activation has a clear modulatory role on mu opioid receptor-mediated actions and thereby affects opioid analgesia, tolerance development, and reward. In addition to opioid modulatory actions, NOP receptor activation has important effects on motor function and other physiologic processes. This review discusses how NOP pharmacology intersects, contrasts, and interacts with the mu opioid receptor in terms of tertiary structure and mechanism of receptor activation; location of receptors in the central nervous system; mechanisms of desensitization and downregulation; cellular actions; intracellular signal transduction pathways; and behavioral actions with respect to analgesia, tolerance, dependence, and reward. This is followed by a discussion of the agonists and antagonists that have most contributed to our current knowledge. Because NOP receptors are highly expressed in brain and spinal cord and NOP receptor activation sometimes synergizes with mu receptor-mediated actions and sometimes opposes them, an understanding of NOP receptor pharmacology in the context of these interactions with the opioid receptors will be crucial to the development of novel therapeutics that engage the NOP receptor

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“…This effect is mediated by the inhibition of GABA release in the VTA via the activation of presynaptic MORs of GABA interneurons or GABA projections from the rostromedial tegmental nucleus (RMTG), which then leads to an increase in DA release in the NAc through a disinhibition mechanism (Johnson and North, 1992;Sánchez-Catalán et al, 2014;Siuda et al, 2015) or local activation of MORs in the NAc core and discrete areas of the NAc shell (Hipó lito et al, 2008). Although clinical and preclinical reports have shown a decrease in DA signaling during pain conditions (Ozaki et al, 2003;Jarcho et al, 2012;Wu et al, 2014), few studies have examined whether this effect may be mediated by alterations in MOR function.…”

Section: Mor Function Is Reduced In the Presence Of Inflammatory Painmentioning

confidence: 99%

Inflammatory Pain Promotes Increased Opioid Self-Administration: Role of Dysregulated Ventral Tegmental Area μ Opioid Receptors

et al. 2015

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Pain management in opioid abusers engenders ethical and practical difficulties for clinicians, often resulting in pain mismanagement. Although chronic opioid administration may alter pain states, the presence of pain itself may alter the propensity to self-administer opioids, and previous history of drug abuse comorbid with chronic pain promotes higher rates of opioid misuse. Here, we tested the hypothesis that inflammatory pain leads to increased heroin self-administration resulting from altered mu opioid receptor (MOR) regulation of mesolimbic dopamine (DA) transmission. To this end, the complete Freund's adjuvant (CFA) model of inflammation was used to assess the neurochemical and functional changes induced by inflammatory pain on MOR-mediated mesolimbic DA transmission and on rat intravenous heroin self-administration under fixed ratio (FR) and progressive ratio (PR) schedules of reinforcement. In the presence of inflammatory pain, heroin intake under an FR schedule was increased for high, but attenuated for low, heroin doses with concomitant alterations in mesolimbic MOR function suggested by DA microdialysis. Consistent with the reduction in low dose FR heroin self-administration, inflammatory pain reduced motivation for a low dose of heroin, as measured by responding under a PR schedule of reinforcement, an effect dissociable from high heroin dose PR responding. Together, these results identify a connection between inflammatory pain and loss of MOR function in the mesolimbic dopaminergic pathway that increases intake of high doses of heroin. These findings suggest that pain-induced loss of MOR function in the mesolimbic pathway may promote opioid dose escalation and contribute to opioid abuse-associated phenotypes.

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Spatiotemporal Control of Opioid Signaling and Behavior

Cited by 127 publications

References 42 publications

Stretchable multichannel antennas in soft wireless optoelectronic implants for optogenetics

Stretchable multichannel antennas in soft wireless optoelectronic implants for optogenetics

Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems

Inflammatory Pain Promotes Increased Opioid Self-Administration: Role of Dysregulated Ventral Tegmental Area μ Opioid Receptors

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