Optogenetics and photopharmacology in pain research and therapeutics

  • Federico Iseppon Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, Gower Street, WC1E 6BT, London, UK. Discovery UK, Neuroscience, Biopharmaceuticals R&D, AstraZeneca, Cambridge, UK.
  • Manuel Arcangeletti Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, Gower Street, WC1E 6BT, London, UK.
Keywords: optogenetics, photopharmacology, pain, phototherapy


Pain afflicts billions of people worldwide, who suffer especially from long-term chronic pain. This gruelling condition affects the nervous system at all levels: from the brain to the spinal cord, the Dorsal Root Ganglia (DRG) and the peripheral fibres innervating the skin. The nature of the different molecular and cellular components of the somatosensory modalities, as well as the complexity of the peripheral and central circuitry are yet poorly understood. Light-based techniques such as optogenetics, in concert with the recent advances in single-cell genetic profiling, can help to elucidate the role of diverse neuronal sub-populations in the encoding of different sensory and painful stimuli by switching these neurons on and off via optically active proteins, namely opsins.  Recently, photopharmacology has emerged from the efforts made to advance optogenetics. The introduction of azo-benzene-based light-sensitive molecular switches has been applied to a wide variety of molecular targets, from ion channels and receptors to transporters, enzymes and many more, some of which are paramount for pain research and therapy.

In this Review, we summarise the recent advances in the fields of optogenetics and photopharmacology and we discuss the use of light-based techniques for the study of acute and chronic pain physiology, as well as their potential for future therapeutic use to improve pain treatment.


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Author Biography

Manuel Arcangeletti, Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, Gower Street, WC1E 6BT, London, UK.

Postdoctoral Research Assistant at the Molecular Nociception Lab at University College London.


Pain terms: a list with definitions and notes on usage. Recommended by the IASP Subcommittee on Taxonomy. Pain. 1979 Jun;6(3):249.

Nahin RL. Estimates of Pain Prevalence and Severity in Adults: United States, 2012. J Pain. 2015 Aug 1;16(8):769–80.

Breivik H, Collett B, Ventafridda V, Cohen R, Gallacher D. Survey of chronic pain in Europe: prevalence, impact on daily life, and treatment. Eur J Pain. 2006 May 20;10(4):287–287.

Todd AJ. Neuronal circuitry for pain processing in the dorsal horn. Nat Rev Neurosci. 2010 Dec;11(12):823–36.

Peirs C, Seal RP. Neural circuits for pain: recent advances and current views. Science. 2016 Nov 4;354(6312):578–84.

von Hehn CA, Baron R, Woolf CJ. Deconstructing the neuropathic pain phenotype to reveal neural mechanisms. Neuron. 2012 Feb 23;73(4):638–52.

Markenson JA. Mechanisms of chronic pain. Am J Med. 1996 Jul 31;101(1 A):S6–18.

Meacham K, Shepherd A, Mohapatra DP, Haroutounian S. Neuropathic pain: central vs. peripheral mechanisms. Curr Pain Headache Rep. 2017 Jun 1;21(6):28.

Saab CY. Chronic pain and brain abnormalities. Chronic Pain and Brain Abnormalities. 2013;1–148.

Usoskin D, Furlan A, Islam S, Abdo H, Lönnerberg P, Lou D, et al. Unbiased classification of sensory neuron types by large-scale single-cell RNA sequencing. Nat Neurosci. 2015 Jan 1;18(1):145–53.

Boyden ES, Zhang F, Bamberg E, Nagel G, Deisseroth K. Millisecond-timescale, genetically targeted optical control of neural activity. Nat Neurosci. 2005;8(9):1263–8.

Paoletti P, Ellis-Davies GCR, Mourot A. Optical control of neuronal ion channels and receptors. Nat Rev Neurosci. 2019 Sep 1;20(9):514–32.

Hüll K, Morstein J, Trauner D. In vivo photopharmacology. Chem Rev. 2018 Nov 14;118(21):10710–47.

Rost BR, Schneider-Warme F, Schmitz D, Hegemann P. Optogenetic tools for subcellular applications in neuroscience. Neuron. 2017 Nov 1;96(3):572–603.

Velema WA, Szymanski W, Feringa BL. Photopharmacology: beyond proof of principle. J Am Chem Soc. 2014 Feb 12;136(6):2178–91.

Lerch MM, Hansen MJ, van Dam GM, Szymanski W, Feringa BL. Emerging targets in photopharmacology. Angew Chem Int Ed. 2016 Sep 5;55(37):10978–99.

Nikolaev DM, Panov MS, Shtyrov AA, Boitsov VM, Vyazmin SY, Chakchir OB, et al. Perspective tools for optogenetics and photopharmacology: from design to implementation. Springer Ser Chem Phys. 2019;119:139–72.

Oesterhelt D, Stoeckenius W. Rhodopsin-like protein from the purple membrane of Halobacterium halobium. Nat New Biol. 1971 Sep 29;233(39):149–52.

Matsuno-Yagi A, Mukohata Y. Two possible roles of bacteriorhodopsin; a comparative study of strains of Halobacterium halobium differing in pigmentation. Biochem Biophys Res Commun. 1977 Sep 9;78(1):237–43.

Nagel G, Ollig D, Fuhrmann M, Kateriya S, Musti AM, Bamberg E, et al. Channelrhodopsin-1: a light-gated proton channel in green algae. Science. 2002 Jun 28;296(5577):2395–8.

Zemelman B V., Lee GA, Ng M, Miesenböck G. Selective photostimulation of genetically chARGed neurons. Neuron. 2002 Jan 3;33(1):15–22.

Lima SQ, Miesenböck G. Remote control of behavior through genetically targeted photostimulation of neurons. Cell. 2005 Apr 8;121(1):141–52.

Banghart M, Borges K, Isacoff E, Trauner D, Kramer RH. Light-activated ion channels for remote control of neuronal firing. Nat Neurosci. 2004 Dec;7(12):1381–6.

Aravanis A, Wang L, Zhang F, Meltzer L, Mogri M, Schneider M, et al. An optical neural interface: in vivo control of rodent motor cortex with integrated fiberoptic and optogenetic technology. J Neural Eng. 2007;4(3):S143–S156.

Tye KM, Deisseroth K. Optogenetic investigation of neural circuits underlying brain disease in animal models. Nat Rev Neurosci. 2012 Apr;13(4):251–66.

Wang H, Vilela M, Winkler A, Tarnawski M, Schlichting I, Yumerefendi H, et al. LOVTRAP: an optogenetic system for photoinduced protein dissociation. Nat Methods. 2016 Aug 30;13(9):755–8.

Berndt A, Lee SY, Ramakrishnan C, Deisseroth K. Structure-guided transformation of channelrhodopsin into a light-activated chloride channel. Science. 2014;344(6182):420–4.

Berndt A, Lee SY, Wietek J, Ramakrishnan C, Steinberg EE, Rashid AJ, et al. Structural foundations of optogenetics: determinants of channelrhodopsin ion selectivity. Proc Natl Acad Sci USA. 2016 Jan 26;113(4):822–9.

Iyer SM, Vesuna S, Ramakrishnan C, Huynh K, Young S, Berndt A, et al. Optogenetic and chemogenetic strategies for sustained inhibition of pain. Sci Rep. 2016 Aug 3;6:30570.

Airan RD, Thompson KR, Fenno LE, Bernstein H, Deisseroth K. Temporally precise in vivo control of intracellular signalling. Nature. 2009 Apr 23;458(7241):1025–9.

Schindler SE, McCall JG, Yan P, Hyrc KL, Li M, Tucker CL, et al. Photo-activatable Cre recombinase regulates gene expression in vivo. Sci Rep. 2015 Sep 9;5:13627.

Jarrin S, Finn DP. Optogenetics and its application in pain and anxiety research. Neurosci Biobehav Rev. 2019 Oct 1;105:200–11.

Bieth J, Vratsanos SM, Wassermann N, Erlanger BF. Photoregulation of biological activity by photocromic reagents. II. Inhibitors of acetylcholinesterase. Proc Natl Acad Sci USA. 1969;64(3):1103–6.

Deal WJ, Erlanger BF, Nachmansohn D. Photoregulation of biological activity by photochromic reagents. 3. Photoregulation of bioelectricity by acetylcholine receptor inhibitors. Proc Natl Acad Sci USA. 1969;64(4):1230–4.

Fehrentz T, Schönberger M, Trauner D. Optochemical genetics. Angew Chem Int Ed. 2011 Dec 16;50(51):12156–82.

Polosukhina A, Litt J, Tochitsky I, Nemargut J, Sychev Y, De Kouchkovsky I, et al. Photochemical restoration of visual responses in blind mice. Neuron. 2012 Jul 26;75(2):271–82.

Laprell L, Hüll K, Stawski P, Schön C, Michalakis S, Biel M, et al. Restoring light sensitivity in blind retinae using a photochromic AMPA receptor agonist. ACS Chem Neurosci. 2016 Jan 20;7(1):15–20.

Miesenböck G. Optogenetic control of cells and circuits. Annu Rev Cell Dev Biol. 2011 Nov 10;27(1):731–58.

Nagel G, Szellas T, Huhn W, Kateriya S, Adeishvili N, Berthold P, et al. Channelrhodopsin-2, a directly light-gated cation-selective membrane channel. Proc Natl Acad Sci USA. 2003 Nov 25;100(SUPPL. 2):13940–5.

Gradinaru V, Mogri M, Thompson KR, Henderson JM, Deisseroth K. Optical deconstruction of parkinsonian neural circuitry. Science. 2009 Apr 17;324(5925):354–9.

Zhang F, Wang LP, Brauner M, Liewald JF, Kay K, Watzke N, et al. Multimodal fast optical interrogation of neural circuitry. Nature. 2007 Apr 5;446(7136):633–9.

Chow BY, Han X, Dobry AS, Qian X, Chuong AS, Li M, et al. High-performance genetically targetable optical neural silencing by light-driven proton pumps. Nature. 2010 Jan 7;463(7277):98–102.

Berndt A, Schoenenberger P, Mattis J, Tye KM, Deisseroth K, Hegemann P, et al. High-efficiency channelrhodopsins for fast neuronal stimulation at low light levels. Proc Natl Acad Sci USA. 2011 May 3;108(18):7595–600.

Gunaydin LA, Yizhar O, Berndt A, Sohal VS, Deisseroth K, Hegemann P. Ultrafast optogenetic control. Nat Neurosci. 2010 Mar;13(3):387–92.

Zhang F, Prigge M, Beyrière F, Tsunoda SP, Mattis J, Yizhar O, et al. Red-shifted optogenetic excitation: a tool for fast neural control derived from Volvox carteri. Nat Neurosci. 2008 Jun;11(6):631–3.

Chuong AS, Miri ML, Busskamp V, Matthews GAC, Acker LC, Sørensen AT, et al. Noninvasive optical inhibition with a red-shifted microbial rhodopsin. Nat Neurosci. 2014;17(8):1123–9.

Berndt A, Yizhar O, Gunaydin LA, Hegemann P, Deisseroth K. Bi-stable neural state switches. Nat Neurosci. 2009 Feb;12(2):229–34.

Oh E, Maejima T, Liu C, Deneris E, Herlitze S. Substitution of 5-HT1A receptor signaling by a light-activated G protein-coupled receptor. J Biol Chem. 2010 Oct 1;285(40):30825–36.

Gunaydin LA, Grosenick L, Finkelstein JC, Kauvar I V., Fenno LE, Adhikari A, et al. Natural neural projection dynamics underlying social behavior. Cell. 2014 Jun 19;157(7):1535–51.

Li P, Rial D, Canas PM, Yoo JH, Li W, Zhou X, et al. Optogenetic activation of intracellular adenosine A2A receptor signaling in the hippocampus is sufficient to trigger CREB phosphorylation and impair memory. Mol Psychiatry. 2015 Nov 1;20(11):1339–49.

van Wyk M, Pielecka-Fortuna J, Löwel S, Kleinlogel S. Restoring the ON switch in blind retinas: opto-mGluR6, a next-generation, cell-tailored optogenetic tool. PLoS Biol. 2015 May 7;13(5):e1002143.

Barish PA, Xu Y, Li J, Sun J, Jarajapu YPR, Ogle WO. Design and functional evaluation of an optically active μ-opioid receptor. Eur J Pharmacol. 2013 Apr 5;705(1–3):42–8.

Siuda ER, Copits BA, Schmidt MJ, Baird MA, Al-Hasani R, Planer WJ, et al. Spatiotemporal Control of Opioid Signaling and Behavior. Neuron. 2015 May 20;86(4):923–35.

Luo L, Callaway EM, Svoboda K. Genetic Dissection of Neural Circuits. Neuron. 2008 Mar 13;57(5):634–60.

Zhang F, Gradinaru V, Adamantidis AR, Durand R, Airan RD, De Lecea L, et al. Optogenetic interrogation of neural circuits: technology for probing mammalian brain structures. Nat Protoc. 2010 Mar;5(3):439–56.

Zeng H, Madisen L. Mouse transgenic approaches in optogenetics. Prog Brain Res. 2012;196:193–213.

Zhang F, Wang LP, Boyden ES, Deisseroth K. Channelrhodopsin-2 and optical control of excitable cells. Nat Methods. 2006 Oct;3(10):785–92.

Nagy A. Cre recombinase: the universal reagent for genome tailoring. Genesis. 2000 Feb 1;26(2):99–109.

Branda CS, Dymecki SM. Talking about a revolution: The impact of site-specific recombinases on genetic analyses in mice. Dev Cell. 2004 Jan;6(1):7–28.

Schnütgen F, Doerflinger N, Calléja C, Wendling O, Chambon P, Ghyselinck NB. A directional strategy for monitoring Cre-mediated recombination at the cellular level in the mouse. Nat Biotechnol. 2003 May 1;21(5):562–5.

Cardin JA, Carlén M, Meletis K, Knoblich U, Zhang F, Deisseroth K, et al. Driving fast-spiking cells induces gamma rhythm and controls sensory responses. Nature. 2009 Jun 4;459(7247):663–7.

Li B, Yang XY, Qian FP, Tang M, Ma C, Chiang LY. A novel analgesic approach to optogenetically and specifically inhibit pain transmission using TRPV1 promoter. Brain Res. 2015;1609(1):12–20.

Daou I, Tuttle AH, Longo G, Wieskopf JS, Bonin RP, Ase AR, et al. Remote optogenetic activation and sensitization of pain pathways in freely moving mice. J Neurosci Res. 2013;33(47):18631–40.

Gong S, Doughty M, Harbaugh CR, Cummins A, Hatten ME, Heintz N, et al. Targeting Cre recombinase to specific neuron populations with bacterial artificial chromosome constructs. J Neurosci Res. 2007 Sep 12;27(37):9817–23.

Beaudry H, Daou I, Ase AR, Ribeiro-Da-Silva A, Séguela P. Distinct behavioral responses evoked by selective optogenetic stimulation of the major TRPV1+ and MrgD+ subsets of C-fibers. Pain. 2017;158(12):2329–39.

Madisen L, Mao T, Koch H, Zhuo JM, Berenyi A, Fujisawa S, et al. A toolbox of Cre-dependent optogenetic transgenic mice for light-induced activation and silencing. Nat Neurosci. 2012 May;15(5):793–802.

Baumbauer KM, Deberry JJ, Adelman PC, Miller RH, Hachisuka J, Lee KH, et al. Keratinocytes can modulate and directly initiate nociceptive responses. eLife. 2015 Sep 2;4:e09674.

Madisen L, Garner AR, Shimaoka D, Chuong AS, Klapoetke NC, Li L, et al. Transgenic mice for intersectional targeting of neural sensors and effectors with high specificity and performance. Neuron. 2015 Mar 4;85(5):942–58.

Bourane S, Duan B, Koch SC, Dalet A, Britz O, Garcia-Campmany L, et al. Gate control of mechanical itch by a subpopulation of spinal cord interneurons. Science. 2015 Oct 30;350(6260):550–4.

Robertson SD, Plummer NW, De Marchena J, Jensen P. Developmental origins of central norepinephrine neuron diversity. Nature Neuroscience. 2013 Aug;16(8):1016–23.

Fenno LE, Mattis J, Ramakrishnan C, Hyun M, Lee SY, He M, et al. Targeting cells with single vectors using multiple-feature Boolean logic. Nat Methods. 2014 Jun 8;11(7):763–72.

Brieke C, Rohrbach F, Gottschalk A, Mayer G, Heckel A. Light-controlled tools. Angew Chem Int Ed. 2012 Aug 20;51(34):8446–76.

Ellis-Davies GCR. Caged compounds: Photorelease technology for control of cellular chemistry and physiology. Nat Methods. 2007 Aug 30;4(8):619–28.

Klán P, Šolomek T, Bochet CG, Blanc A, Givens R, Rubina M, et al. Photoremovable protecting groups in chemistry and biology: reaction mechanisms and efficacy. Chem Rev. 2013 Jan 9;113(1):119–91.

Broichhagen J, Frank JA, Trauner D. A Roadmap to success in photopharmacology. Acc Chem Res. 2015 Jul 21;48(7):1947–60.

Mutter NL, Volarić J, Szymanski W, Feringa BL, Maglia G. Reversible photocontrolled nanopore assembly. J Am Chem Soc. 2019 Sep 11;141(36):14356–63.

Morstein J, Trauner D. New players in phototherapy: photopharmacology and bio-integrated optoelectronics. Curr Opin Chem Biol. 2019 Jun 1;50:145–51.

Mehta ZB, Johnston NR, Nguyen-Tu MS, Broichhagen J, Schultz P, Larner DP, et al. Remote control of glucose homeostasis in vivo using photopharmacology. Sci Rep. 2017;7(1):291.

Yeoh YQ, Yu J, Polyak SW, Horsley JR, Abell AD. Photopharmacological control of cyclic antimicrobial peptides. Chembiochem. 2018 Dec 18;19(24):2591–7.

Sansalone L, Bratsch-Prince J, Tang S, Captain B, Mott DD, Raymo FM. Photopotentiation of the GABAA receptor with caged diazepam. Proc Natl Acad Sci USA. 2019 Oct 15;116(42):21176–84.

Qazi R, Gomez AM, Castro DC, Zou Z, Sim JY, Xiong Y, et al. Wireless optofluidic brain probes for chronic neuropharmacology and photostimulation. Nat Biomed Eng. 2019 Aug 1;3(8):655–69.

Mayer G, Hechel A. Biologically active molecules with a “light switch.” Angew Chem Int Ed. 2006 Jul 24;45(30):4900–21.

Gautier A, Gauron C, Volovitch M, Bensimon D, Jullien L, Vriz S. How to control proteins with light in living systems. Nat Chem Biol. 2014;10(7):533–41.

Kamiya H. Photochemical inactivation analysis of temporal dynamics of postsynaptic native AMPA receptors in hippocampal slices. J Neurosci. 2012 May 9;32(19):6517–24.

Hansen MJ, Velema WA, Lerch MM, Szymanski W, Feringa BL. Wavelength-selective cleavage of photoprotecting groups: Strategies and applications in dynamic systems. Chem Soc Rev. 2015 Jun 7;44(11):3358–77.

Peterson JA, Wijesooriya C, Gehrmann EJ, Mahoney KM, Goswami PP, Albright TR, et al. Family of BODIPY Photocages Cleaved by Single Photons of Visible/Near-Infrared Light. J Am Chem Soc. 2018 Jun 13;140(23):7343–6.

Jedlitzke B, Yilmaz Z, Dörner W, Mootz HD. Photobodies: light-activatable single-domain antibody fragments. Angew Chem Int Ed. 2020 Jan 20;59(4):1506–10.

Hermanson GT. Bioconjugate techniques: 3rd edn. Elsevier Inc.; 2013. p. 229–58.

Krishnamurthy VM, Semetey V, Bracher PJ, Shen N, Whitesides GM. Dependence of effective molarity on linker length for an intramolecular protein-ligand system. J Am Chem Soc. 2007 Feb 7;129(5):1312–20.

Yasuike N, Lu H, Xia P, Woolley GA. Intramolecular cross-linking of proteins with azobenzene-based cross-linkers. Methods Enzymol. 2019 Jan 1;624:129–49.

Gazerani P. Shedding light on photo-switchable analgesics for pain. Pain management. 2017 Mar 1;7(2):71–4.

Carr FB, Zachariou V. Nociception and pain: Lessons from optogenetics. Front Behav Neurosci. 2014 Mar 25;8:69.

Tovote P, Fadok JP, Lüthi A. Neuronal circuits for fear and anxiety. Nat Rev Neurosci. 2015 Jun 26;16(6):317–31.

Corder G, Ahanonu B, Grewe BF, Wang D, Schnitzer MJ, Scherrer G. An amygdalar neural ensemble that encodes the unpleasantness of pain. Science. 2019 Jan 18;363(6424):276–81.

Kiritoshi T, Ji G, Neugebauer V. Rescue of impaired mGluR5-driven endocannabinoid signaling restores prefrontal cortical output to inhibit pain in arthritic rats. J Neurosci. 2016 Jan 20;36(3):837–50.

Zhang Z, Gadotti VM, Chen L, Souza IA, Stemkowski PL, Zamponi GW. Role of prelimbic GABAergic circuits in sensory and emotional aspects of neuropathic pain. Cell Rep. 2015 Aug 4;12(5):752–9.

Huang J, Gadotti VM, Chen L, Souza IA, Huang S, Wang D, et al. A neuronal circuit for activating descending modulation of neuropathic pain. Nat Neurosci. 2019 Oct 1;22(10):1659–68.

Mcdonald AJ. Cortical pathways to the mammalian amygdala. Prog Neurobiol. 1998 Jun 27;55(3):257–332.

Neugebauer V. Amygdala pain mechanisms. Handb Exp Pharmacol. 2015;227:261–84.

Bernard JF, Besson JM. The spino(trigemino)pontoamygdaloid pathway: electrophysiological evidence for an involvement in pain processes. J Neurophysiol. 1990;63(3):473–90.

Sugimura YK, Takahashi Y, Watabe AM, Kato F. Synaptic and network consequences of monosynaptic nociceptive inputs of parabrachial nucleus origin in the central amygdala. J Neurophysiol. 2016 Jun 1;115(6):2721–39.

Crock LW, Kolber BJ, Morgan CD, Sadler KE, Vogt SK, Bruchas MR, et al. Central amygdala metabotropic glutamate receptor 5 in the modulation of visceral pain. J Neurosci. 2012 Oct 10;32(41):14217–26.

Li JN, Sheets PL. Spared nerve injury differentially alters parabrachial monosynaptic excitatory inputs to molecularly specific neurons in distinct subregions of the central amygdala. Pain. 2020 Jan 1;161(1):166–76.

Abraira VE, Ginty DD. The sensory neurons of touch. Neuron. 2013 Aug 21;79(4):618–39.

Montgomery KL, Iyer SM, Christensen AJ, Deisseroth K, Delp SL. Beyond the brain: optogenetic control in the spinal cord and peripheral nervous system. Sci Transl Med. 2016 May 4;8(337).

Wang H, Zylka MJ. Mrgprd-expressing polymodal nociceptive neurons innervate most known classes of substantia gelatinosa neurons. J Neurosci. 2009 Oct 21;29(42):13202–9.

Park S Il, Brenner DS, Shin G, Morgan CD, Copits BA, Chung HU, et al. Soft, stretchable, fully implantable miniaturized optoelectronic systems for wireless optogenetics. Nat Biotechnol. 2015 Dec 1;33(12):1280–6.

Mishra SK, Tisel SM, Orestes P, Bhangoo SK, Hoon MA. TRPV1-lineage neurons are required for thermal sensation. EMBO J. 2011 Feb 2;30(3):582–93.

Samineni VK, Yoon J, Crawford KE, Jeong YR, McKenzie KC, Shin G, et al. Fully implantable, battery-free wireless optoelectronic devices for spinal optogenetics. Pain. 2017 Nov 1;158(11):2108–16.

Iyer SM, Montgomery KL, Towne C, Lee SY, Ramakrishnan C, Deisseroth K, et al. Virally mediated optogenetic excitation and inhibition of pain in freely moving nontransgenic mice. Nat Biotechnol. 2014;32(3):274–8.

Daou I, Beaudry H, Ase AR, Wieskopf JS, Ribeiro-da-Silva A, Mogil JS, et al. Optogenetic silencing of Nav1.8-positive afferents alleviates inflammatory and neuropathic pain. eNeuro. 2016;3(1):702–5.

Draxler P, Honsek SD, Forsthuber L, Hadschieff V, Sandkühler J. VGluT3+ primary afferents play distinct roles in mechanical and cold hypersensitivity depending on pain etiology. J Neurosci. 2014 Sep 3;34(36):12015–28.

Bonin RP, Wang F, Desrochers-Couture M, Ga¸secka A, Boulanger ME, Côté DC, et al. Epidural optogenetics for controlled analgesia. Mol Pain. 2016 Feb 27;12.

Ghitani N, Barik A, Szczot M, Thompson JH, Li C, Le Pichon CE, et al. Specialized mechanosensory nociceptors mediating rapid responses to hair pull. Neuron. 2017 Aug 16;95(4):944-954.e4.

Maksimovic S, Nakatani M, Baba Y, Nelson AM, Marshall KL, Wellnitz SA, et al. Epidermal Merkel cells are mechanosensory cells that tune mammalian touch receptors. Nature. 2014;509(7502):617–21.

Moehring F, Cowie AM, Menzel AD, Weyer AD, Grzybowski M, Arzua T, et al. Keratinocytes mediate innocuous and noxious touch via ATP-P2X4 signaling. eLife. 2018 Jan 16;7.

Skerratt SE, West CW. Ion channel therapeutics for pain. Channels. 2015 Jan 1;9(6):344–51.

Zussy C, Gómez-Santacana X, Rovira X, De Bundel D, Ferrazzo S, Bosch D, et al. Dynamic modulation of inflammatory pain-related affective and sensory symptoms by optical control of amygdala metabotropic glutamate receptor 4. Mol Psychiatry. 2018 Mar 1;23(3):509–20.

Frias B, Merighi A. Capsaicin, nociception and pain. Molecules. 2016 Jun 1;21(6).

Frank JA, Moroni M, Moshourab R, Sumser M, Lewin GR, Trauner D. Photoswitchable fatty acids enable optical control of TRPV1. Nat Commun. 2015 May 22;6.

Konrad DB, Frank JA, Trauner D. Synthesis of redshifted azobenzene photoswitches by late-stage functionalization. Chem Eur J. 2016 Mar 18;22(13):4364–8.

Gilbert D, Funk K, Dekowski B, Lechler R, Keller S, Möhrlen F, et al. Caged capsaicins: new tools for the examination of TRPV1 channels in somatosensory neurons. Chembiochem. 2007 Jan;8(1):89–97.

Kokel D, Cheung CYJ, Mills R, Coutinho-Budd J, Huang L, Setola V, et al. Photochemical activation of TRPA1 channels in neurons and animals. Nat Chem Biol. 2013 Apr;9(4):257–63.

Fajardo O, Friedrich RW. Optopharmacology: A light switch for pain. Nat Chem Biol. 2013 Apr;9(4):219–20.

Lam PY, Mendu SK, Mills RW, Zheng B, Padilla H, Milan DJ, et al. A high-conductance chemo-optogenetic system based on the vertebrate channel Trpa1b. Sci Rep. 2017 Dec 1;7(1):11839.

Leinders-Zufall T, Storch U, Bleymehl K, Mederos y Schnitzler M, Frank JA, Konrad DB, et al. PhoDAGs enable optical control of diacylglycerol-sensitive transient receptor potential channels. Cell Chem Biol. 2018 Feb 15;25(2):215-223.e3.

Lichtenegger M, Tiapko O, Svobodova B, Stockner T, Glasnov TN, Schreibmayer W, et al. An optically controlled probe identifies lipid-gating fenestrations within the TRPC3 channel article. Nat Chem Biol. 2018 Apr 1;14(4):396–404.

Stein M, Middendorp SJ, Carta V, Pejo E, Raines DE, Forman SA, et al. Azo-propofols: photochromic potentiators of GABA a receptors. Angew Chem Int Ed. 2012 Oct 15;51(42):10500–4.

Lutz T, Wein T, Höfner G, Pabel J, Eder M, Dine J, et al. Development of new photoswitchable azobenzene based γ-aminobutyric acid (GABA) uptake inhibitors with distinctly enhanced potency upon photoactivation. J Med Chem. 2018 Jul 26;61(14):6211–35.

Lin WC, Davenport CM, Mourot A, Vytla D, Smith CM, Medeiros KA, et al. Engineering a light-regulated GABAA receptor for optical control of neural inhibition. ACS Chem Biol. 2014 Jul 18;9(7):1414–9.

Lin WC, Tsai MC, Davenport CM, Smith CM, Veit J, Wilson NM, et al. A comprehensive optogenetic pharmacology toolkit for in vivo control of GABAA receptors and synaptic inhibition. Neuron. 2015 Dec 2;88(5):879–91.

McKenzie CK, Sanchez-Romero I, Janovjak H. Flipping the photoswitch: ion channels under light control. Adv Exp Med Biol. 2015;869:101–17.

Mourot A, Tochitsky I, Kramer RH. Light at the end of the channel: optical manipulation of intrinsic neuronal excitability with chemical photoswitches. Front Mol Neurosci. 2013 Mar 6;6:5.

Mourot A, Fehrentz T, Le Feuvre Y, Smith CM, Herold C, Dalkara D, et al. Rapid optical control of nociception with an ion-channel photoswitch. Nat Methods. 2012 Apr;9(4):396–402.

Binshtok AM, Gerner P, Oh SB, Puopolo M, Suzuki S, Roberson DP, et al. Coapplication of lidocaine and the permanently charged sodium channel blocker QX-314 produces a long-lasting nociceptive blockade in rodents. Anesthesiology. 2009;111(1):127–37.

Schoenberger M, Damijonaitis A, Zhang Z, Nagel D, Trauner D. Development of a new photochromic ion channel blocker via azologization of fomocaine. ACS Chem Neurosci. 2014 Jul 16;5(7):514–8.

Mourot A, Herold C, Kienzler MA, Kramer RH. Understanding and improving photo-control of ion channels in nociceptors with azobenzene photo-switches. Br J Pharmacol. 2018 Jun 1;175(12):2296–311.

Römpler H, Stäubert C, Thor D, Schulz A, Hofreiter M, Schöneberg T. G protein-coupled time travel: evolutionary aspects of GPCR research. Mol Interv. 2007 Feb;7(1):17–25.

Schönberger M, Trauner D. A photochromic agonist for μ-opioid receptors. Angew Chem Int Ed. 2014 Mar 17;53(12):3264–7.

Levitz J, Popescu AT, Reiner A, Isacoff EY. A toolkit for orthogonal and in vivo optical manipulation of ionotropic glutamate receptors. Front Mol Neurosci. 2016 Feb 2;9:2.

Goudet C, Rovira X, Llebaria A. Shedding light on metabotropic glutamate receptors using optogenetics and photopharmacology. Curr Opin Pharmacol. 2018 Feb 1;38:8–15.

Levitz J, Broichhagen J, Leippe P, Konrad D, Trauner D, Isacoff EY. Dual optical control and mechanistic insights into photoswitchable group II and III metabotropic glutamate receptors. Proc Natl Acad Sci USA. 2017 Apr 25;114(17):E3546–54.

Mickle AD, Gereau RW. A bright future? Optogenetics in the periphery for pain research and therapy. Pain. 2018 Sep 1;159:S65–73.

Copits BA, Pullen MY, Gereau RW. Spotlight on pain: Optogenetic approaches for interrogating somatosensory circuits. Pain. 2016 Aug 19;157(11):2424–33.

Christensen AJ, Iyer SM, François A, Vyas S, Ramakrishnan C, Vesuna S, et al. In Vivo Interrogation of Spinal Mechanosensory Circuits. Cell Rep. 2016 Nov 1;17(6):1699–710.

Towne C, Montgomery KL, Iyer SM, Deisseroth K, Delp SL. Optogenetic Control of Targeted Peripheral Axons in Freely Moving Animals. PLoS ONE. 2013 Aug 21;8(8).

Montgomery KL, Yeh AJ, Ho JS, Tsao V, Iyer SM, Grosenick L, et al. Wirelessly powered, fully internal optogenetics for brain, spinal and peripheral circuits in mice. Nat Methods. 2015 Sep 29;12(10):969–74.

Samineni VK, Mickle AD, Yoon J, Grajales-Reyes JG, Pullen MY, Crawford KE, et al. Optogenetic silencing of nociceptive primary afferents reduces evoked and ongoing bladder pain. Sci Rep. 2017 Dec 1;7(1).

Shin G, Gomez AM, Al-Hasani R, Jeong YR, Kim J, Xie Z, et al. Flexible Near-Field Wireless Optoelectronics as subdermal implants for broad applications in optogenetics. Neuron. 2017 Feb 8;93(3):509-521.e3.

Lu L, Gutruf P, Xia L, Bhatti DL, Wang X, Vazquez-Guardado A, et al. Wireless optoelectronic photometers for monitoring neuronal dynamics in the deep brain. Proc Natl Acad Sci USA. 2018 Feb 13;115(7):E1374–83.

Beaudry H, Daou I, Ribeiro-da-Silva A, Séguéla P. Will optogenetics be used to treat chronic pain patients? Pain Manag. 2017 Jul 1;7(4):269–78.

Stein M, Breit A, Fehrentz T, Gudermann T, Trauner D. Optical control of TRPV1 channels. Angew Chem Int Ed. 2013 Sep 9;52(37):9845–8.

Font J, López-Cano M, Notartomaso S, Scarselli P, Di Pietro P, Bresolí-Obach R, et al. Optical control of pain in vivo with a photoactive mGlu5 receptor negative allosteric modulator. eLife. 2017 Apr 11;6.

Golden RN, Gaynes BN, Ekstrom RD, Hamer RM, Jacobsen FM, Suppes T, et al. The efficacy of light therapy in the treatment of mood disorders: a review and meta-analysis of the evidence. Am J Psychiatry. 2005 Apr;162(4):656–62.

Figueiro MG, Plitnick BA, Lok A, Ejones GE, Higgins P, Rhornick TR, et al. Tailored lighting intervention improves measures of sleep, depression, and agitation in persons with Alzheimer’s disease and related dementia living in long-term care facilities. Clin Interv Aging. 2014 Sep 12;9:1527–37.

Ibrahim MM, Patwardhan A, Gilbraith KB, Moutal A, Yang X, Chew LA, et al. Long-lasting antinociceptive effects of green light in acute and chronic pain in rats. Pain. 2017 Feb 1;158(2):347–60.

Park S Il, Shin G, McCall JG, Al-Hasani R, Norrisf A, Xia L, et al. Stretchable multichannel antennas in soft wireless optoelectronic implants for optogenetics. Proc Natl Acad Sci USA. 2016 Dec 13;113(50):E8169–77.

Kim T Il, McCall JG, Jung YH, Huang X, Siuda ER, Li Y, et al. Injectable, cellular-scale optoelectronics with applications for wireless optogenetics. Science. 2013 Apr 12;340(6129):211–6.

Jeong JW, McCall JG, Shin G, Zhang Y, Al-Hasani R, Kim M, et al. Wireless optofluidic systems for programmable in vivo pharmacology and optogenetics. Cell. 2015 Aug 1;162(3):662–74.

Chattopadhyay M, Mata M, Fink DJ. Vector-mediated release of GABA attenuates pain-related behaviors and reduces Na V1.7 in DRG neurons. Eur J Pain. 2011 Oct;15(9):913–20.

Braz J, Beaufour C, Coutaux A, Epstein AL, Cesselin F, Hamon M, et al. Therapeutic efficacy in experimental polyarthritis of viral-driven enkephalin overproduction in sensory neurons. J Neurosci. 2001 Oct 15;21(20):7881–8.

Fink DJ, Wechuck J, Mata M, Glorioso JC, Goss J, Krisky D, et al. Gene therapy for pain: results of a phase I clinical trial. Ann Neurol. 2011 Aug;70(2):207–12.

Wolfe D, Mata M, Fink DJ. A human trial of HSV-mediated gene transfer for the treatment of chronic pain. Gene Ther. 2009;16(4):455–60.

How to Cite
Iseppon, F., & Arcangeletti, M. (2020). Optogenetics and photopharmacology in pain research and therapeutics. STEMedicine, 1(3), e43. https://doi.org/10.37175/stemedicine.v1i3.43
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