Involvement of the lateral hypothalamic peptide orexin in morphine dependence and withdrawal
Open accessAbstract
The lateral hypothalamus (LH) is implicated in the behavioral actions of drugs of abuse, but the cellular and molecular basis of this role is unclear. Recent identification of neuropeptides localized in LH neurons has allowed for more specific studies of LH function. The LH-specific peptide orexin (hypocretin) has been shown to be important in arousal and sleep regulation. However, orexin cells of the LH project broadly throughout the brain such that orexin may influence other behaviors as well. In this study, we show that orexin neurons, and not nearby LH neurons expressing melanin-concentrating hormone (MCH), have mu-opioid receptors and respond to chronic morphine administration and opiate antagonist-precipitated morphine withdrawal. cAMP response element-mediated transcription is induced in a subset of orexin cells, but not MCH cells, after exposure to chronic morphine or induction of withdrawal. Additionally, c-Fos and the orexin gene itself are induced in orexin cells in the LH during morphine withdrawal. Finally, we show that orexin knock-out mice develop attenuated morphine dependence, as indicated by a less severe antagonist-precipitated withdrawal syndrome. Together, these studies support a role for the orexin system in molecular adaptations to morphine, and demonstrate dramatic differences in molecular responses among different populations of LH neurons.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Sakurai, T., Amemiya, A., Ishii, M., Matsuzaki, I., Chemelli, R. M., Tanaka, H., Williams, S. C., Richardson, J. A., Kozlowski, G. P., Wilson, S., et al. (1998) · Cell · doi:10.1016/s0092-8674(00)80949-6 · Cited by 5,501 · see citing works
Self-citationNeurons containing hypocretin (orexin) project to multiple neuronal systems
Peyron, C., Tighe, D. K., van den Pol, A. N., de Lecea, L., Heller, H. C., Sutcliffe, J. G., & Kilduff, T. S. (1998) · The Journal of Neuroscience · doi:10.1523/jneurosci.18-23-09996.1998 · Cited by 3,466 · see citing works
Olds, J., & Milner, P. (1954) · Journal of Comparative and Physiological Psychology · doi:10.1037/h0058775 · Cited by 3,176 · see citing works
Narcolepsy in orexin Knockout Mice
Chemelli, R. M., Willie, J. T., Sinton, C. M., Elmquist, J. K., Scammell, T., Lee, C., Richardson, J. A., Williams, S. C., Xiong, Y., Kisanuki, Y., et al. (1999) · Cell · doi:10.1016/s0092-8674(00)81973-x · Cited by 3,095 · see citing works
Self-citationMolecular basis of long-term plasticity underlying addiction
Nestler, E. J. (2001) · Nature reviews. Neuroscience · doi:10.1038/35053570 · Cited by 1,857 · see citing works
Self-citationOrexin A activates locus coeruleus cell firing and increases arousal in the rat
Hagan, J. J., Leslie, R. A., Patel, S., Evans, M. L., Wattam, T. A., Holmes, S., Benham, C. D., Taylor, S. G., Routledge, C., Hemmati, P., et al. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.19.10911 · Cited by 1,234 · see citing works
Hypothalamic control of food intake in rats and cats.
Anand, B. K., & Brobeck, J. R. (1951) · PubMed · Cited by 1,197 · see citing works
Mice lacking melanin-concentrating hormone are hypophagic and lean
Shimada, M., Tritos, N. A., Lowell, B. B., Flier, J. S., & Maratos–Flier, E. (1998) · Nature · doi:10.1038/25341 · Cited by 1,152 · see citing works
Sheng, M., McFadden, G., & Greenberg, M. E. (1990) · Neuron · doi:10.1016/0896-6273(90)90115-v · Cited by 1,076 · see citing works
Mansour, A., Khachaturian, H., Lewis, M. E. S., Akil, H., & Watson, S. J. (1988) · Pain · doi:10.1016/0304-3959(88)90103-0 · Cited by 973 · see citing works
Stimulation of cAMP response element (CRE)-mediated transcription during contextual learning
Impey, S., Smith, D. M., Obrietan, K. H., Donahue, R. J., Wade, C. B., & Storm, D. R. (1998) · Nature Neuroscience · doi:10.1038/2830 · Cited by 520 · see citing works
Hypocretin-1 Modulates Rapid Eye Movement Sleep through Activation of Locus Coeruleus Neurons
Bourgin, P., Huitrón‐Reséndiz, S., Spier, A. D., Fabre, V., Morte, B., Criado, J. R., Sutcliffe, J. G., Henriksen, S. J., & de Lecea, L. (2000) · Journal of Neuroscience · doi:10.1523/jneurosci.20-20-07760.2000 · Cited by 508 · see citing works
Fadel, J. R., & Deutch, A. Y. (2002) · Neuroscience · doi:10.1016/s0306-4522(02)00017-9 · Cited by 503 · see citing works
Edwards, C., Abusnana, S., Sunter, D., Murphy, K. G., Ghatei, M. A., & Bloom, S. R. (1999) · Journal of Endocrinology · doi:10.1677/joe.0.160r007 · Cited by 433 · see citing works
Orexin (Hypocretin) Neurons Contain Dynorphin
Chou, T. C., Lee, C. E., Lü, J., Elmquist, J. K., Hara, J., Willie, J. T., Beuckmann, C. T., Chemelli, R. M., Sakurai, T., Yanagisawa, M., et al. (2001) · Journal of Neuroscience · doi:10.1523/jneurosci.21-19-j0003.2001 · Cited by 430 · see citing works
Self-citationRegulation of camp-inducible genes by creb
Montminy, M., González, G., & Yamamoto, K. K. (1990) · Trends in Neurosciences · doi:10.1016/0166-2236(90)90045-c · Cited by 419 · see citing works
Nakamura, T., Uramura, K., Nambu, T., Yada, T., Goto, K., Yanagisawa, M., & Sakurai, T. (2000) · Brain Research · doi:10.1016/s0006-8993(00)02555-5 · Cited by 352 · see citing works
Self-citationA Golgi study of the descending medial forebrain bundle
Millhouse, O. E. (1969) · Brain Research · doi:10.1016/0006-8993(69)90161-9 · Cited by 345 · see citing works
A portrait of the substrate for self-stimulation.
Gallistel, C. R., Shizgal, P., & Yeomans, J. S. (1981) · Psychological Review · doi:10.1037/0033-295x.88.3.228 · Cited by 337 · see citing works
Hypothalamic orexin expression: modulation by blood glucose and feeding.
Cai, X., Widdowson, P. S., Harrold, J. A., Wilson, S., Buckingham, R. E., Arch, J. R. S., Tadayyon, M., Clapham, J. C., Wilding, J. P. H., & Williams, G. H. (1999) · Diabetes · doi:10.2337/diabetes.48.11.2132 · Cited by 320 · see citing works
μ-Opioid receptor mRNA expression in the rat CNS: comparison to μ-receptor binding
Mansour, A., Fox, C. A., Thompson, R. C., Akil, H., & Watson, S. J. (1994) · Brain Research · doi:10.1016/0006-8993(94)90031-0 · Cited by 304 · see citing works
Haynes, A. C., Jackson, B., Overend, P., Buckingham, R. E., Wilson, S., Tadayyon, M., & Arch, J. R. S. (1999) · Peptides · doi:10.1016/s0196-9781(99)00105-9 · Cited by 303 · see citing works
Centrally administered orexin/hypocretin activates HPA axis in rats
Kuru, M., Ueta, Y., Serino, R., Nakazato, M., Yamamoto, Y., Shibuya, I., & Yamashita, H. (2000) · Neuroreport · doi:10.1097/00001756-200006260-00034 · Cited by 285 · see citing works
Possible Involvement of Orexin in the Stress Reaction in Rats
Ida, T., Nakahara, K., Murakami, T., Hanada, R., Nakazato, M., & Murakami, N. (2000) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2000.2412 · Cited by 268 · see citing works
Melanin-concentrating hormone: a functional melanocortin antagonist in the hypothalamus
Ludwig, D. S., Mountjoy, K. G., Tatro, J. B., Gillette, J. A., Frederich, R. C., Flier, J. S., & Maratos–Flier, E. (1998) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1998.274.4.e627 · Cited by 220 · see citing works
Delfs, J. M., Kong, H., Mestek, A., Chen, Y., Yu, L., Reisine, T., & Chesselet, M. (1994) · The Journal of Comparative Neurology · doi:10.1002/cne.903450104 · Cited by 218 · see citing works
Induction of chronic Fos-related antigens in rat brain by chronic morphine administration.
Nye, H. E., & Nestler, E. J. (1996) · Molecular Pharmacology · doi:10.1016/s0026-895x(25)08777-2 · Cited by 212 · see citing works
Self-citationShaw-Lutchman, T. Z., Barrot, M., Wallace, T. L., Gilden, L., Zachariou, V., Impey, S., Duman, R. S., Storm, D. R., & Nestler, E. J. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-09-03663.2002 · Cited by 205 · see citing works
Self-citationLeptin Regulation of Prepro-orexin and Orexin Receptor mRNA Levels in the Hypothalamus
López, M., Seoane, L. M., Garcia, M. D. C., Lago, F., Casanueva, F. F., Señarís, R. M., & Diéguez, C. (2000) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2000.2245 · Cited by 195 · see citing works
Differential Activation of Orexin Neurons by Antipsychotic Drugs Associated with Weight Gain
Fadel, J. R., Bubser, M., & Deutch, A. Y. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-15-06742.2002 · Cited by 192 · see citing works
Hayward, M. D., Duman, R. S., & Nestler, E. J. (1990) · Brain Research · doi:10.1016/0006-8993(90)90872-9 · Cited by 181 · see citing works
Self-citationEating Elicited by Orexin-A, But Not Melanin-Concentrating Hormone, Is Opioid Mediated
Clegg, D. J., Air, E. L., Woods, S. C., & Seeley, R. J. (2002) · Endocrinology · doi:10.1210/endo.143.8.8977 · Cited by 160 · see citing works
Min, N., JOH, T. H., Kim, K. S., Peng, C., & Son, J. H. (1994) · Molecular Brain Research · doi:10.1016/0169-328x(94)90011-6 · Cited by 125 · see citing works
Gracy, K. N. (2001) · Neuropsychopharmacology · doi:10.1016/s0893-133x(00)00186-x · Cited by 124 · see citing works
Nguyen, T., Kobierski, L. A., Comb, M. J., & Hyman, S. E. (1990) · Journal of Neuroscience · doi:10.1523/jneurosci.10-08-02825.1990 · Cited by 120 · see citing works
Morphine Enhances Lateral Hypothalamic Self-Stimulation in the Rat
Adams, W. J., Lorens, S. A., & Mitchell, C. L. (1972) · Experimental Biology and Medicine · doi:10.3181/00379727-140-36549 · Cited by 97 · see citing works
Self-administration of D-Ala2-Met-enkephalinamide at hypothalamic self-stimulation sites
OLDS, M. E., & Williams, K. (1980) · Brain Research · doi:10.1016/0006-8993(80)91325-6 · Cited by 73 · see citing works
Goodall, E. B., & Carey, R. J. (1975) · Journal of Comparative and Physiological Psychology · doi:10.1037/h0077187 · Cited by 60 · see citing works
Georges, F. E., Stinus, L., & Moine, C. L. (2000) · European Journal of Neuroscience · doi:10.1046/j.0953-816x.2000.01334.x · Cited by 56 · see citing works
Self-administration of morphine into the lateral hypothalamus in the mouse
Cazala, P., Darracq, C., & Saint-Marc, M. (1987) · Brain Research · doi:10.1016/0006-8993(87)90908-5 · Cited by 52 · see citing works
Intracranial self-stimulation as a technique to study the reward properties of drugs of abuse
Bozarth, M. A., Gerber, G. J., & Wise, R. A. (1980) · Pharmacology Biochemistry and Behavior · doi:10.1016/s0091-3057(80)80037-2 · Cited by 36 · see citing works
A Transgenic Mouse Model to Study Transsynaptic Regulation of Tyrosine Hydroxylase Gene Expression
Min, N., JOH, T. H., Baker, H. A., Cubells, J. F., & Son, J. H. (1996) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1996.67010011.x · Cited by 31 · see citing works
Intrinsic neurons are involved in lateral hypothalamic self-stimulation
Velley, L., Chaminade, C., Roy, M. T., Kempf, E., & Cardo, B. (1983) · Brain Research · doi:10.1016/0006-8993(83)90391-8 · Cited by 28 · see citing works
Briski, K. P., & Sylvester, P. W. (2001) · Neuroscience Letters · doi:10.1016/s0304-3940(01)01826-2 · Cited by 15 · see citing works
Intracranial self-stimulation as a technique to study the reward properties of drugs of abuse
Bozarth, M. A., Gerber, G. J., & Wise, R. A. (1980) · Drug and Alcohol Dependence · doi:10.1016/0376-8716(80)90416-0 · Cited by 3 · see citing works
Horvath (1999) · doi:10.1002/(sici)1096-9861(19991213)415:2
Flagged first, then by citations
Cited by
Sorted by citations
A role for lateral hypothalamic orexin neurons in reward seeking
Harris, G. C., Wimmer, M., & Aston-Jones, G. (2005) · Nature · doi:10.1038/nature04071 · Cited by 1,311 · see citing works
The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness
Sakurai, T. (2007) · Nature Reviews Neuroscience · doi:10.1038/nrn2092 · Cited by 1,276 · see citing works
Molecular mechanisms of drug addiction
Nestler, E. J. (2004) · Neuropharmacology · doi:10.1016/j.neuropharm.2004.06.031 · Cited by 1,108 · see citing works
Self-citationBorgland, S. L., Taha, S. A., Sarti, F., Fields, H. L., & Bonci, A. (2006) · Neuron · doi:10.1016/j.neuron.2006.01.016 · Cited by 718 · see citing works
Narcolepsy — clinical spectrum, aetiopathophysiology, diagnosis and treatment
Bassetti, C. L., Adamantidis, A., Burdakov, D., Han, F., Gay, S., Kallweit, U., Khatami, R., Koning, F., Kornum, B. R., Lammers, G. J., et al. (2019) · Nature Reviews Neurology · doi:10.1038/s41582-019-0226-9 · Cited by 651 · see citing works
Arousal and reward: a dichotomy in orexin function
Harris, G. C., & Aston‐Jones, G. (2006) · Trends in Neurosciences · doi:10.1016/j.tins.2006.08.002 · Cited by 565 · see citing works
Role for hypocretin in mediating stress-induced reinstatement of cocaine-seeking behavior
Boutrel, B., Kenny, P. J., Specio, S. E., Martin-Fardon, R., Markou, A., Koob, G. F., & de Lecea, L. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0507480102 · Cited by 520 · see citing works
Narita, M., Nagumo, Y., Hashimoto, S., Narita, M., Khotib, J., Miyatake, M., Sakurai, T., Yanagisawa, M., Nakamachi, T., Shioda, S., et al. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.2761-05.2006 · Cited by 516 · see citing works
Self-citationCellular neuroadaptations to chronic opioids: tolerance, withdrawal and addiction
Christie, M. J. (2008) · British Journal of Pharmacology · doi:10.1038/bjp.2008.100 · Cited by 481 · see citing works
Orexin/Hypocretin: A Neuropeptide at the Interface of Sleep, Energy Homeostasis, and Reward System
Tsujino, N., & Sakurai, T. (2009) · Pharmacological Reviews · doi:10.1124/pr.109.001321 · Cited by 479 · see citing works
The role of orexin in motivated behaviours
Sakurai, T. (2014) · Nature reviews. Neuroscience · doi:10.1038/nrn3837 · Cited by 466 · see citing works
Lateral hypothalamic orexin/hypocretin neurons: A role in reward-seeking and addiction
Aston‐Jones, G., Smith, R. J., Sartor, G. C., Moorman, D. E., Massi, L., Tahsili‐Fahadan, P., & Richardson, K. A. (2009) · Brain Research · doi:10.1016/j.brainres.2009.09.106 · Cited by 386 · see citing works
Orexin Receptors: Pharmacology and Therapeutic Opportunities
Scammell, T. E., & Winrow, C. J. (2011) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010510-100528 · Cited by 379 · see citing works
Neuroplasticity Mediated by Altered Gene Expression
McClung, C. A., & Nestler, E. J. (2008) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301544 · Cited by 347 · see citing works
Self-citationAfferents to the GABAergic tail of the ventral tegmental area in the rat
Kaufling, J., Veinante, P., Pawlowski, S. A., Freund‐Mercier, M., & Barrot, M. (2009) · Journal of Comparative Neurology · doi:10.1002/cne.21983 · Cited by 347 · see citing works
Self-citationGeorgescu, D., Sears, R. M., Hommel, J. D., Barrot, M., Bolaños, C. A., Marsh, D. J., Bednarek, M. A., Bibb, J. A., Maratos–Flier, E., Nestler, E. J., et al. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.1714-04.2005 · Cited by 346 · see citing works
Self-citationDrug Addiction: Hyperkatifeia/Negative Reinforcement as a Framework for Medications Development
Koob, G. F. (2021) · Pharmacological Reviews · doi:10.1124/pharmrev.120.000083 · Cited by 337 · see citing works
Mu opioid receptor: a gateway to drug addiction
Contet, C., Kieffer, B. L., & Befort, K. (2004) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2004.05.005 · Cited by 340 · see citing works
Local gene knockdown in the brain using viral-mediated RNA interference
Hommel, J. D., Sears, R. M., Georgescu, D., Simmons, D. L., & DiLeone, R. J. (2003) · Nature Medicine · doi:10.1038/nm964 · Cited by 334 · see citing works
Self-citationRole of lateral hypothalamic orexin neurons in reward processing and addiction
Aston‐Jones, G., Smith, R. J., Moorman, D. E., & Richardson, K. A. (2008) · Neuropharmacology · doi:10.1016/j.neuropharm.2008.06.060 · Cited by 330 · see citing works
Control of hypothalamic orexin neurons by acid and CO 2
Williams, R. H., Jensen, L. T., Verkhratsky, A., Fugger, L. H., & Burdakov, D. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0702676104 · Cited by 284 · see citing works
The neurobiological basis of narcolepsy
Mahoney, C. E., Cogswell, A., Koralnik, I. J., & Scammell, T. E. (2019) · Nature Reviews Neuroscience · doi:10.1038/s41583-018-0097-x · Cited by 289 · see citing works
Opioids: cellular mechanisms of tolerance and physical dependence
Bailey, C. P., & Connor, M. A. (2004) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2004.08.012 · Cited by 285 · see citing works
Orexin neuronal circuitry: Role in the regulation of sleep and wakefulness
Ohno, K., & Sakurai, T. (2007) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2007.08.001 · Cited by 269 · see citing works
Role of orexin in modulating arousal, feeding, and motivation
Tsujino, N., & Sakurai, T. (2013) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2013.00028 · Cited by 259 · see citing works
Berthoud, H.-R., & Münzberg, H. (2011) · Physiology & Behavior · doi:10.1016/j.physbeh.2011.04.051 · Cited by 248 · see citing works
Essential role for RGS9 in opiate action
Zachariou, V., Georgescu, D., Sanchez, N., Rahman, Z. U., Dileone, R., Berton, O., Neve, R. L., Sim‐Selley, L. J., Selley, D. E., Gold, S. J., et al. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2232594100 · Cited by 250 · see citing works
Self-citationEspaña, R. A., Oleson, E. B., Locke, J. L., Brookshire, B. R., Roberts, D. C. S., & Jones, S. R. (2009) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2009.07065.x · Cited by 250 · see citing works
Zheng, H., Patterson, L. M., & Berthoud, H.-R. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.3542-07.2007 · Cited by 248 · see citing works
Orexin Signaling Mediates the Antidepressant-Like Effect of Calorie Restriction
Lutter, M., Krishnan, V., Russo, S. J., Jung, S., McClung, C. A., & Nestler, E. J. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.5584-07.2008 · Cited by 234 · see citing works
Self-citationLateral hypothalamic neuropeptides in reward and drug addiction
Dileone, R., Georgescu, D., & Nestler, E. J. (2003) · Life Sciences · doi:10.1016/s0024-3205(03)00408-9 · Cited by 220 · see citing works
Self-citationMultiple roles for orexin/hypocretin in addiction
Mahler, S. V., Smith, R. J., Moorman, D. E., Sartor, G. C., & Aston-Jones, G. (2012) · Progress in Brain Research · doi:10.1016/b978-0-444-59489-1.00007-0 · Cited by 215 · see citing works
Smith, R. J., & Aston-Jones, G. (2008) · Brain Structure and Function · doi:10.1007/s00429-008-0191-3 · Cited by 206 · see citing works
Insulin, leptin, and food reward: update 2008
Figlewicz, D. P., & Benoit, S. C. (2008) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.90725.2008 · Cited by 202 · see citing works
Harris, G. C. M., Wimmer, M. A., Randall-Thompson, J., & Aston‐Jones, G. (2007) · Behavioural Brain Research · doi:10.1016/j.bbr.2007.05.025 · Cited by 195 · see citing works
James, M. H., Stopper, C. M., Zimmer, B. A., Koll, N. E., Bowrey, H. E., & Aston‐Jones, G. (2018) · Biological Psychiatry · doi:10.1016/j.biopsych.2018.07.022 · Cited by 191 · see citing works
Orexin/hypocretin role in reward: implications for opioid and other addictions
Baimel, C., Bartlett, S. E., Chiou, L., Lawrence, A. J., Muschamp, J. W., Patkar, O. L., Tung, L.-W., & Borgland, S. L. (2014) · British Journal of Pharmacology · doi:10.1111/bph.12639 · Cited by 180 · see citing works
A Decade of Orexin/Hypocretin and Addiction: Where Are We Now?
James, M. H., Mahler, S. V., Moorman, D. E., & Aston‐Jones, G. (2016) · Current topics in behavioral neurosciences · doi:10.1007/7854_2016_57 · Cited by 171 · see citing works
Gotter, A. L., Webber, A. L., Coleman, P. J., Renger, J. J., & Winrow, C. J. (2012) · Pharmacological Reviews · doi:10.1124/pr.111.005546 · Cited by 162 · see citing works
Schwartz, S., Ponz, A., Poryazova, R., Werth, E., Boesiger, P., Khatami, R., & Bassetti, C. L. (2007) · Brain · doi:10.1093/brain/awm292 · Cited by 160 · see citing works
Xu, T., Yang, Y., Ward, R. J., Gao, L., & Liu, Y. (2013) · Cellular Signalling · doi:10.1016/j.cellsig.2013.07.025 · Cited by 158 · see citing works
Shoblock, J. R., Welty, N., Aluisio, L. E., Fraser, I. C., Motley, S. T., Morton, K. L., Palmer, J. A., Bonaventure, P., Carruthers, N. I., Lovenberg, T. W., et al. (2010) · Psychopharmacology · doi:10.1007/s00213-010-2127-x · Cited by 156 · see citing works
Li, Y., & van den Pol, A. N. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.3380-06.2006 · Cited by 141 · see citing works
Sharf, R., Sarhan, M., & Dileone, R. (2008) · Biological Psychiatry · doi:10.1016/j.biopsych.2008.03.006 · Cited by 144 · see citing works
Self-citationStress and Arousal: The Corticotrophin-Releasing Factor/Hypocretin Circuitry
Winsky‐Sommerer, R., Boutrel, B., & de Lecea, L. (2005) · Molecular Neurobiology · doi:10.1385/mn:32:3:285 · Cited by 144 · see citing works
Buisman‐Pijlman, F. T. A., Sumracki, N. M., Gordon, J. J., Hull, P. R., Carter, C. S., & Mattie Tops, A. (2013) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2013.09.005 · Cited by 143 · see citing works
Orexin B/hypocretin 2 increases glutamatergic transmission to ventral tegmental area neurons
Borgland, S. L., Storm, E. E., & Bonci, A. (2008) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2008.06397.x · Cited by 141 · see citing works
Moorman, D. E., & Aston‐Jones, G. (2009) · Alcohol · doi:10.1016/j.alcohol.2009.07.002 · Cited by 140 · see citing works
Thannickal, T. C., John, J., Shan, L., Swaab, D. F., Wu, M.-F., Ramanathan, L., McGregor, R., Chew, K., Cornford, M. E., Yamanaka, A., et al. (2018) · Science Translational Medicine · doi:10.1126/scitranslmed.aao4953 · Cited by 138 · see citing works
Stamatakis, A. M., Sparta, D. R., Jennings, J. H., McElligott, Z. A., Decot, H., & Stuber, G. D. (2014) · Neuropharmacology · doi:10.1016/j.neuropharm.2013.05.046 · Cited by 132 · see citing works
Orexin/hypocretin is necessary for context-driven cocaine-seeking
Smith, R. J., Tahsili‐Fahadan, P., & Aston‐Jones, G. (2009) · Neuropharmacology · doi:10.1016/j.neuropharm.2009.06.042 · Cited by 131 · see citing works
Inflammation-Induced Lethargy Is Mediated by Suppression of Orexin Neuron Activity
Grossberg, A. J., Zhu, X., Leinninger, G. M., Levasseur, P. R., Braun, T. P., Myers, M. G., & Marks, D. L. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.2311-11.2011 · Cited by 130 · see citing works
The discovery of suvorexant, the first orexin receptor drug for insomnia
Coleman, P. J., Gotter, A. L., Herring, W. J., Winrow, C. J., & Renger, J. J. (2017) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010716-104837 · Cited by 128 · see citing works
Zhou, Y., Bendor, J., Hofmann, L., Randesi, M., Ho, A., & Kreek, M. J. (2006) · Journal of Endocrinology · doi:10.1677/joe.1.06960 · Cited by 130 · see citing works
Pharmacological characterization of MK-6096 – A dual orexin receptor antagonist for insomnia
Winrow, C. J., Gotter, A. L., Cox, C. D., Tannenbaum, P. L., Garson, S. L., Doran, S. M., Breslin, M. J., Schreier, J. D., Fox, S. V., Harrell, C. M., et al. (2011) · Neuropharmacology · doi:10.1016/j.neuropharm.2011.10.003 · Cited by 127 · see citing works
The role of hypocretin in driving arousal and goal-oriented behaviors
Boutrel, B., Cannella, N., & de Lecea, L. (2009) · Brain Research · doi:10.1016/j.brainres.2009.11.054 · Cited by 125 · see citing works
Morphine-induced Changes of Gene Expression in the Brain
Ammon-Treiber, S., & Höllt, V. (2004) · Addiction Biology · doi:10.1080/13556210412331308994 · Cited by 124 · see citing works
Smith, R. J., & Aston‐Jones, G. (2012) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2012.08013.x · Cited by 121 · see citing works
Sarchielli, P., Rainero, I., Coppola, F., Rossi, C., Mancini, M. L., Pinessi, L., & Calabresi, P. (2008) · Cephalalgia · doi:10.1111/j.1468-2982.2008.01566.x · Cited by 114 · see citing works
Huang, H., Acuna, C., Li, Y., Cheng, H. M., Obrietan, K. H., & van den Pol, A. N. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.0732-07.2007 · Cited by 112 · see citing works
A role for hypocretin/orexin in motivation
Thompson, J. L., & Borgland, S. L. (2010) · Behavioural Brain Research · doi:10.1016/j.bbr.2010.09.028 · Cited by 110 · see citing works
Energy regulatory signals and food reward
Figlewicz, D. P., & Sipols, A. J. (2010) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2010.03.002 · Cited by 111 · see citing works
Brain Reward Circuits in Morphine Addiction
Kim, J., Ham, S., Hong, H., Moon, C., & Im, H. (2016) · Molecules and Cells · doi:10.14348/molcells.2016.0137 · Cited by 113 · see citing works
Abnormal activity in reward brain circuits in human narcolepsy with cataplexy
Ponz, A., Khatami, R., Poryazova, R., Werth, E., Boesiger, P., Bassetti, C. L., & Schwartz, S. (2009) · Annals of Neurology · doi:10.1002/ana.21825 · Cited by 109 · see citing works
Role of orexin/hypocretin in dependence and addiction
Sharf, R., Sarhan, M., & Dileone, R. (2009) · Brain Research · doi:10.1016/j.brainres.2009.08.028 · Cited by 110 · see citing works
Self-citationGABAB receptor‐mediated modulation of hypocretin/orexin neurones in mouse hypothalamus
Xie, X., Crowder, T. L., Yamanaka, A., Morairty, S. R., LeWinter, R. D., Sakurai, T., & Kilduff, T. S. (2006) · The Journal of Physiology · doi:10.1113/jphysiol.2006.108266 · Cited by 104 · see citing works
de Lecea, L., & Sutcliffe, J. G. (2005) · The FEBS Journal · doi:10.1111/j.1742-4658.2005.04981.x · Cited by 105 · see citing works
Local network regulation of orexin neurons in the lateral hypothalamus
Burt, J., Alberto, C. O., Parsons, M. P., & Hirasawa, M. (2011) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00674.2010 · Cited by 103 · see citing works
Shining light on wakefulness and arousal
de Lecea, L., Carter, M. E., & Adamantidis, A. (2012) · Biological Psychiatry · doi:10.1016/j.biopsych.2012.01.032 · Cited by 103 · see citing works
Ghrelin Interacts with Neuropeptide Y Y1 and Opioid Receptors to Increase Food Reward
Skibicka, K. P., Shirazi, R. H., Hansson, C., & Dickson, S. L. (2011) · Endocrinology · doi:10.1210/en.2011-1606 · Cited by 103 · see citing works
Orexin Signaling Via the Orexin 1 Receptor Mediates Operant Responding for Food Reinforcement
Sharf, R., Sarhan, M., Brayton, C. E., Guarnieri, D. J., Taylor, J. R., & Dileone, R. (2010) · Biological Psychiatry · doi:10.1016/j.biopsych.2009.12.035 · Cited by 100 · see citing works
Self-citationμ-Opioid Receptor-Mediated Depression of the Hypothalamic Hypocretin/Orexin Arousal System
Li, Y., & van den Pol, A. N. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.5447-07.2008 · Cited by 101 · see citing works
Forebrain networks and the control of feeding by environmental learned cues
Petrovich, G. D. (2013) · Physiology & Behavior · doi:10.1016/j.physbeh.2013.03.024 · Cited by 100 · see citing works
Leptin modulates nutrient reward via inhibitory galanin action on orexin neurons
Laque, A., Yu, S., Qualls‐Creekmore, E., Gettys, S., Schwartzenburg, C., Bui, K., Rhodes, C. J., Berthoud, H., Morrison, C. D., Richards, B. K. S., et al. (2015) · Molecular Metabolism · doi:10.1016/j.molmet.2015.07.002 · Cited by 99 · see citing works
Hypocretin (orexin) neuromodulation of stress and reward pathways
Giardino, W. J., & de Lecea, L. (2014) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2014.07.006 · Cited by 101 · see citing works
Bidirectional Relationship between Opioids and Disrupted Sleep: Putative Mechanisms
Eacret, D., Veasey, S. C., & Blendy, J. A. (2020) · Molecular Pharmacology · doi:10.1124/mol.119.119107 · Cited by 95 · see citing works
Orexin receptors as therapeutic drug targets
Gotter, A. L., Roecker, A. J., Hargreaves, R. J., Coleman, P. J., Winrow, C. J., & Renger, J. J. (2012) · Progress in brain research · doi:10.1016/b978-0-444-59489-1.00010-0 · Cited by 99 · see citing works
Excessive opioid use and the development of chronic migraine
BIGAL, M. E., & Lipton, R. B. (2009) · Pain · doi:10.1016/j.pain.2009.01.013 · Cited by 99 · see citing works
Addiction and arousal: The hypocretin connection
Boutrel, B., & de Lecea, L. (2007) · Physiology & Behavior · doi:10.1016/j.physbeh.2007.11.022 · Cited by 99 · see citing works
Neurobiology of hyperactivity and reward: Agreeable restlessness in Anorexia Nervosa
Scheurink, A. J. W., Boersma, G. J., Nergårdh, R., & Södersten, P. (2010) · Physiology & Behavior · doi:10.1016/j.physbeh.2010.03.016 · Cited by 99 · see citing works
Chen, S. A., O'Dell, L. E., Hoefer, M. E., Greenwell, T. N., Zorrilla, E. P., & Koob, G. F. (2006) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301008 · Cited by 97 · see citing works
Orexin mediates morphine place preference, but not morphine-induced hyperactivity or sensitization
Sharf, R., Guarnieri, D. J., Taylor, J. R., & Dileone, R. (2009) · Brain Research · doi:10.1016/j.brainres.2009.12.035 · Cited by 96 · see citing works
Self-citationPhysiological arousal: a role for hypothalamic systems
Adamantidis, A., & de Lecea, L. (2008) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-008-7521-8 · Cited by 95 · see citing works
Neurobehavioral meaning of pupil size
Grujic, N., Polanía, R. H., & Burdakov, D. (2024) · Neuron · doi:10.1016/j.neuron.2024.05.029 · Cited by 93 · see citing works
LeSage, M. G., Perry, J. L., Kotz, C. M., Shelley, D., & Corrigall, W. A. (2010) · Psychopharmacology · doi:10.1007/s00213-010-1792-0 · Cited by 84 · see citing works
The Hypocretin/Orexin System: An Increasingly Important Role in Neuropsychiatry
Chen, Q., de Lecea, L., Hu, Z., & Gao, D. (2014) · Medicinal Research Reviews · doi:10.1002/med.21326 · Cited by 84 · see citing works
Prince, C. D., Rau, A. R., Yorgason, J. T., & España, R. A. (2014) · ACS Chemical Neuroscience · doi:10.1021/cn500246j · Cited by 82 · see citing works
Plaza‐Zabala, A., Flores, Á., Maldonado, R. J., & Berrendero, F. (2011) · Biological Psychiatry · doi:10.1016/j.biopsych.2011.06.025 · Cited by 81 · see citing works
Morganstern, I., Chang, G., Barson, J. R., Ye, Z., Karatayev, O., & Leibowitz, S. F. (2010) · Alcoholism Clinical and Experimental Research · doi:10.1111/j.1530-0277.2010.01161.x · Cited by 79 · see citing works
Calipari, E. S., & España, R. A. (2012) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2012.00054 · Cited by 78 · see citing works
Huhn, A. S., Finan, P. H., Gamaldo, C. E., Hammond, A. S., Umbricht, A., Bergeria, C. L., Strain, E. C., & Dunn, K. E. (2022) · Science Translational Medicine · doi:10.1126/scitranslmed.abn8238 · Cited by 79 · see citing works
The role of orexin-1 receptor signaling in demand for the opioid fentanyl
Fragale, J. E. C., Pantazis, C. B., James, M. H., & Aston‐Jones, G. (2019) · Neuropsychopharmacology · doi:10.1038/s41386-019-0420-x · Cited by 75 · see citing works
Individual differences in orexin‐I receptor modulation of motivation for the opioid remifentanil
Porter‐Stransky, K. A., Bentzley, B. S., & Aston‐Jones, G. (2015) · Addiction Biology · doi:10.1111/adb.12323 · Cited by 74 · see citing works
Matzeu, A., Zamora-Martinez, E. R., & Martin‐Fardon, R. (2014) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2014.00117 · Cited by 81 · see citing works
Winrow, C. J., Tanis, K. Q., Reiss, D. R., Rigby, A. M., Uslaner, J. M., Uebele, V. N., Doran, S. M., Fox, S. V., Garson, S. L., Gotter, A. L., et al. (2009) · Neuropharmacology · doi:10.1016/j.neuropharm.2009.07.008 · Cited by 75 · see citing works
Neural mechanisms underlying obesity and drug addiction
Trinko, R., Sears, R. M., Guarnieri, D. J., & Dileone, R. (2007) · Physiology & Behavior · doi:10.1016/j.physbeh.2007.01.001 · Cited by 75 · see citing works
Self-citationLimbic hyperconnectivity in the vegetative state
Perri, C. D., Bastianello, S., Bartsch, A. J., Pistarini, C., Maggioni, G., Magrassi, L., Imberti, R., Pichiecchio, A., Vitali, P., Laureys, S., et al. (2013) · Neurology · doi:10.1212/wnl.0b013e3182a43b78 · Cited by 75 · see citing works
Srinivasan, S., Simms, J. A., Nielsen, C. K., Lieske, S. P., Bito‐Onon, J. J., Yi, H. Y., Hopf, F. W., Bonci, A., & Bartlett, S. E. (2012) · PLoS ONE · doi:10.1371/journal.pone.0044726 · Cited by 73 · see citing works
Su, L., Luo, R., Liu, Q., Su, J.-R., Yang, L.-X., Ding, Y., Xu, L., & Yao, Y. (2017) · Autophagy · doi:10.1080/15548627.2017.1332549 · Cited by 72 · see citing works
Petrovich, G. D., Hobin, M., & Reppucci, C. J. (2012) · Neuroscience · doi:10.1016/j.neuroscience.2012.08.036 · Cited by 71 · see citing works
- Authors
- Georgescu, D., Zachariou, V., Barrot, M., Mieda, M., Willie, J. T., Eisch, A. J., Yanagisawa, M., Nestler, E. J., & DiLeone, R. J.
- Affiliations
- Howard Hughes Medical Institute (US)
- The University of Texas Southwestern Medical Center (US)
- Centre National de la Recherche Scientifique (FR)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2003-04-15
- Volume
- 23
- Issue
- 8
- Pages
- 3106-3111
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6742290
- OpenAlex
- W2099485542
- Cited by
- 373
- References
- 46
- Citations by year
- 2026: 4 · 2025: 11 · 2024: 16 · 2023: 15 · 2022: 16 · 2021: 12 · 2020: 18 · 2019: 10 · 2018: 20 · 2017: 10 · 2016: 20 · 2015: 15 · 2014: 19 · 2013: 19 · 2012: 27
- FWCI
- 4.17
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- orexin, lateral hypothalamus, morphine dependence, morphine withdrawal, mu-opioid receptor, melanin-concentrating hormone, cAMP response element, c-fos, orexin knockout mice, opioid use disorder, neuronal gene expression
- MeSH terms
- Orexins, Animals, Carrier Proteins, Chronic Disease, Disease Models, Animal, Drug Implants, Gene Expression Regulation, Homozygote, Hypothalamic Hormones, Hypothalamus, Lac Operon, Male, Melanins, Mice, Transgenic, Morphine, Morphine Dependence, Motor Activity, Neurons, Neuropeptides, Pituitary Hormones, Substance Withdrawal Syndrome, Proto-Oncogene Proteins c-fos, Receptors, Opioid, mu, Genes, Reporter, Receptors, Neuropeptide, Mice, Knockout, Response Elements, Receptors, G-Protein-Coupled, Intracellular Signaling Peptides and Proteins, Mice, Orexin Receptors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
