Humans; Rats; Mice; Animals; Eye Movements; Hyperalgesia/complications; Rats, Sprague-Dawley; Sleep; Disease Models, Animal; Nociceptors; Neuralgia; General Medicine
Abstract :
[en] Spontaneous pain, a major complaint of patients with neuropathic pain, has eluded study because there is no reliable marker in either preclinical models or clinical studies. Here, we performed a comprehensive electroencephalogram/electromyogram analysis of sleep in several mouse models of chronic pain: neuropathic (spared nerve injury and chronic constriction injury), inflammatory (Freund's complete adjuvant and carrageenan, plantar incision) and chemical pain (capsaicin). We find that peripheral axonal injury drives fragmentation of sleep by increasing brief arousals from non-rapid eye movement sleep (NREMS) without changing total sleep amount. In contrast to neuropathic pain, inflammatory or chemical pain did not increase brief arousals. NREMS fragmentation was reduced by the analgesics gabapentin and carbamazepine, and it resolved when pain sensitivity returned to normal in a transient neuropathic pain model (sciatic nerve crush). Genetic silencing of peripheral sensory neurons or ablation of CGRP+ neurons in the parabrachial nucleus prevented sleep fragmentation, whereas pharmacological blockade of skin sensory fibers was ineffective, indicating that the neural activity driving the arousals originates ectopically in primary nociceptor neurons and is relayed through the lateral parabrachial nucleus. These findings identify NREMS fragmentation by brief arousals as an effective proxy to measure spontaneous neuropathic pain in mice.
Alexandre, Chloe ; Department of Neurosurgery, Neurosurgery Pain Research Institute, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA ; Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
Miracca, Giulia; Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA ; FM Kirby Neurobiology Center, Boston Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA
Holanda, Victor Duarte ; Department of Neurosurgery, Neurosurgery Pain Research Institute, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA ; Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
Sharma, Ashley; Department of Neurosurgery, Neurosurgery Pain Research Institute, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA ; Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
Kourbanova, Kamila; Department of Neurosurgery, Neurosurgery Pain Research Institute, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA ; Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
Ferreira, Ashley ; Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA ; FM Kirby Neurobiology Center, Boston Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA
Bicca, Maíra A; Department of Neurosurgery, Neurosurgery Pain Research Institute, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA ; Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
Zeng, Xiangsunze; FM Kirby Neurobiology Center, Boston Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA
Nassar, Victoria A; Department of Neurosurgery, Neurosurgery Pain Research Institute, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA ; Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
Lee, Seungkyu ; FM Kirby Neurobiology Center, Boston Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA
Kaur, Satvinder ; Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA
Sarma, Sridevi V; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21205, USA
Sacré, Pierre ; Université de Liège - ULiège > Département d'électricité, électronique et informatique (Institut Montefiore) > Robotique intelligente
Scammell, Thomas E ; Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA
Woolf, Clifford J ; FM Kirby Neurobiology Center, Boston Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA
Latremoliere, Alban ; Department of Neurosurgery, Neurosurgery Pain Research Institute, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA ; Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
N. Attal, C. Fermanian, J. Fermanian, M. Lanteri-Minet, H. Alchaar, D. Bouhassira, Neuropathic pain: Are there distinct subtypes depending on the aetiology or anatomical lesion? Pain 138, 343–353 (2008). non-cancer pain: A systematic review and meta-analysis. Sleep Med. Rev. 57, 101467 (2021).
M. M. Backonja, B. Stacey, Neuropathic pain symptoms relative to overall pain rating. J. Pain 5, 491–497 (2004).
R. Baron, A. Binder, G. Wasner, Neuropathic pain: Diagnosis, pathophysiological mechanisms, and treatment. Lancet Neurol. 9, 807–819 (2010).
M. Devor, Ectopic discharge in Abeta afferents as a source of neuropathic pain. Exp. Brain Res. 196, 115–128 (2009).
L. Djouhri, S. Koutsikou, X. Fang, S. McMullan, S. N. Lawson, Spontaneous pain, both neuropathic and inflammatory, is related to frequency of spontaneous firing in intact C-fiber nociceptors. J. Neurosci. 26, 1281–1292 (2006).
D. L. Tanelian, M. B. MacIver, Analgesic concentrations of lidocaine suppress tonic A-delta and C fiber discharges produced by acute injury. Anesthesiology 74, 934–936 (1991).
N. B. Finnerup, N. Attal, in The Oxford Handbook of the Neurobiology of Pain, J. N. Wood, Ed. (Oxford University Press, 2020), pp. 659–678.
M. Thakur, A. H. Dickenson, R. Baron, Osteoarthritis pain: Nociceptive or neuropathic? Nat. Rev. Rheumatol. 10, 374–380 (2014).
D. A. Walsh, D. F. McWilliams, Mechanisms, impact and management of pain in rheumatoid arthritis. Nat. Rev. Rheumatol. 10, 581–592 (2014).
D. J. Hunter, J. J. McDougall, F. J. Keefe, The symptoms of osteoarthritis and the genesis of pain. Rheum. Dis. Clin. North Am. 34, 623–643 (2008).
N. S. Buch, E. Qerama, N. Brix Finnerup, L. Nikolajsen, Neuromas and postamputation pain. Pain 161, 147–155 (2020).
I. Tracey, C. J. Woolf, N. A. Andrews, Composite pain biomarker signatures for objective assessment and effective treatment. Neuron 101, 783–800 (2019).
K. Deseure, H. Adriaensen, Nonevoked facial pain in rats following infraorbital nerve injury: A parametric analysis. Physiol. Behav. 81, 595–604 (2004).
K. Deseure, G. Hans, Behavioral study of non-evoked orofacial pain following different types of infraorbital nerve injury in rats. Physiol. Behav. 138, 292–296 (2015).
K. Deseure, G. H. Hans, Differential drug effects on spontaneous and evoked pain behavior in a model of trigeminal neuropathic pain. J. Pain Res. 10, 279–286 (2017).
B. P. Vos, A. M. Strassman, R. J. Maciewicz, Behavioral evidence of trigeminal neuropathic pain following chronic constriction injury to the rat's infraorbital nerve. J. Neurosci. 14, 2708–2723 (1994).
L. E. Browne, A. Latremoliere, B. P. Lehnert, A. Grantham, C. Ward, C. Alexandre, M. Costigan, F. Michoud, D. P. Roberson, D. D. Ginty, C. J. Woolf, Time-resolved fast mammalian behavior reveals the complexity of protective pain responses. Cell Rep. 20, 89–98 (2017).
M. C. Henrich, K. S. Frahm, R. C. Coghill, O. K. Andersen, Spinal nociception is facilitated during cognitive distraction. Neuroscience 491, 134–145 (2022).
V. Legrain, J. M. Guerit, R. Bruyer, L. Plaghki, Attentional modulation of the nociceptive processing into the human brain: Selective spatial attention, probability of stimulus occurrence, and target detection effects on laser evoked potentials. Pain 99, 21–39 (2002).
J. S. Mogil, Animal models of pain: Progress and challenges. Nat. Rev. Neurosci. 10, 283–294 (2009).
D. J. Langford, A. L. Bailey, M. L. Chanda, S. E. Clarke, T. E. Drummond, S. Echols, S. Glick, J. Ingrao, T. Klassen-Ross, M. L. Lacroix-Fralish, L. Matsumiya, R. E. Sorge, S. G. Sotocinal, J. M. Tabaka, D. Wong, A. M. van den Maagdenberg, M. D. Ferrari, K. D. Craig, J. S. Mogil, Coding of facial expressions of pain in the laboratory mouse. Nat. Methods 7, 447–449 (2010).
J. S. Mogil, D. S. J. Pang, G. G. Silva Dutra, C. T. Chambers, The development and use of facial grimace scales for pain measurement in animals. Neurosci. Biobehav. Rev. 116, 480–493 (2020).
T. King, L. Vera-Portocarrero, T. Gutierrez, T. W. Vanderah, G. Dussor, J. Lai, H. L. Fields, F. Porreca, Unmasking the tonic-aversive state in neuropathic pain. Nat. Neurosci. 12, 1364–1366 (2009).
A. S. C. Rice, N. B. Finnerup, H. I. Kemp, G. L. Currie, R. Baron, Sensory profiling in animal models of neuropathic pain: A call for back-translation. Pain 159, 819–824 (2018).
G. J. Norman, K. Karelina, N. Zhang, J. C. Walton, J. S. Morris, A. C. Devries, Stress and IL-1beta contribute to the development of depressive-like behavior following peripheral nerve injury. Mol. Psychiatry 15, 404–414 (2010).
C. B. Sieberg, C. Taras, A. Gomaa, C. Nickerson, C. Wong, C. Ward, G. Baskozos, D. L. H. Bennett, J. D. Ramirez, A. C. Themistocleous, A. S. C. Rice, P. R. Shillo, S. Tesfaye, R. R. Edwards, N. A. Andrews, C. Berde, M. Costigan, Neuropathic pain drives anxiety behavior in mice, results consistent with anxiety levels in diabetic neuropathy patients. Pain Rep. 3, e651 (2018).
W. Zhou, Y. Jin, Q. Meng, X. Zhu, T. Bai, Y. Tian, Y. Mao, L. Wang, W. Xie, H. Zhong, N. Zhang, M. H. Luo, W. Tao, H. Wang, J. Li, J. Li, B. S. Qiu, J. N. Zhou, X. Li, H. Xu, K. Wang, X. Zhang, Y. Liu, G. Richter-Levin, L. Xu, Z. Zhang, A neural circuit for comorbid depressive symptoms in chronic pain. Nat. Neurosci. 22, 1649–1658 (2019).
T. Miettinen, P. Mantyselka, N. Hagelberg, S. Mustola, E. Kalso, J. Lotsch, Machine learning suggests sleep as a core factor in chronic pain. Pain 162, 109–123 (2021).
Y. Sun, I. Laksono, J. Selvanathan, A. Saripella, M. Nagappa, C. Pham, M. Englesakis, P. Peng, C. M. Morin, F. Chung, Prevalence of sleep disturbances in patients with chronic
D. C. Turk, R. H. Dworkin, D. Revicki, G. Harding, L. B. Burke, D. Cella, C. S. Cleeland, P. Cowan, J. T. Farrar, S. Hertz, M. B. Max, B. A. Rappaport, Identifying important outcome domains for chronic pain clinical trials: An IMMPACT survey of people with pain. Pain 137, 276–285 (2008).
M. F. Bjurstrom, M. R. Irwin, Polysomnographic characteristics in nonmalignant chronic pain populations: A review of controlled studies. Sleep Med. Rev. 26, 74–86 (2016).
F. Chouchou, S. Khoury, J. M. Chauny, R. Denis, G. J. Lavigne, Postoperative sleep disruptions: A potential catalyst of acute pain? Sleep Med. Rev. 18, 273–282 (2014).
H. Kehlet, T. S. Jensen, C. J. Woolf, Persistent postsurgical pain: Risk factors and prevention. Lancet 367, 1618–1625 (2006).
R. Cardis, S. Lecci, L. M. Fernandez, A. Osorio-Forero, P. C. S. Chung, S. Fulda, I. Decosterd, A. Luthi, Cortico-autonomic local arousals and heightened somatosensory arousability during NREMS of mice in neuropathic pain. eLife 10, e65835 (2021).
H. Ito, E. Navratilova, B. Vagnerova, M. Watanabe, C. Kopruszinski, L. H. Moreira de Souza, X. Yue, D. Ikegami, A. Moutal, A. Patwardhan, R. Khanna, M. Yamazaki, M. Guerrero, H. Rosen, E. Roberts, V. Neugebauer, D. W. Dodick, F. Porreca, Chronic pain recruits hypothalamic dynorphin/kappa opioid receptor signalling to promote wakefulness and vigilance. Brain 146, 1186–1199 (2023).
Y. Y. Liu, D. Yin, L. Chen, W. M. Qu, C. R. Chen, M. Laudon, N. N. Cheng, Y. Urade, Z. L. Huang, Piromelatine exerts antinociceptive effect via melatonin, opioid, and 5HT1A receptors and hypnotic effect via melatonin receptors in a mouse model of neuropathic pain. Psychopharmacology 231, 3973–3985 (2014).
M. Narita, K. Niikura, K. Nanjo-Niikura, M. Narita, M. Furuya, A. Yamashita, M. Saeki, Y. Matsushima, S. Imai, T. Shimizu, M. Asato, N. Kuzumaki, D. Okutsu, K. Miyoshi, M. Suzuki, Y. Tsukiyama, M. Konno, K. Yomiya, M. Matoba, T. Suzuki, Sleep disturbances in a neuropathic pain-like condition in the mouse are associated with altered GABAergic transmission in the cingulate cortex. Pain 152, 1358–1372 (2011).
Y. E. Wu, Y. D. Li, Y. J. Luo, T. X. Wang, H. J. Wang, S. N. Chen, W. M. Qu, Z. L. Huang, Gelsemine alleviates both neuropathic pain and sleep disturbance in partial sciatic nerve ligation mice. Acta Pharmacol. Sin. 36, 1308–1317 (2015).
H. Zhou, M. Li, R. Zhao, L. Sun, G. Yang, A sleep-active basalocortical pathway crucial for generation and maintenance of chronic pain. Nat. Neurosci. 26, 458–469 (2023).
A. Ho, S. J. Lee, V. J. Drew, J. Jung, J. Kang, C. Cheong, T. Kim, Sleep disturbance correlated with severity of neuropathic pain in sciatic nerve crush injury model. J. Sleep Res. , e14137 (2024).
M. L. Andersen, S. Tufik, Sleep patterns over 21-day period in rats with chronic constriction of sciatic nerve. Brain Res. 984, 84–92 (2003).
V. K. Kontinen, A. Ahnaou, W. H. Drinkenburg, T. F. Meert, Sleep and EEG patterns in the chronic constriction injury model of neuropathic pain. Physiol. Behav. 78, 241–246 (2003).
L. J. Leys, K. L. Chu, J. Xu, M. Pai, H. S. Yang, H. M. Robb, M. F. Jarvis, R. J. Radek, S. McGaraughty, Disturbances in slow-wave sleep are induced by models of bilateral inflammation, neuropathic, and postoperative pain, but not osteoarthritic pain in rats. Pain 154, 1092–1102 (2013).
C. R. Monassi, R. Bandler, K. A. Keay, A subpopulation of rats show social and sleep-waking changes typical of chronic neuropathic pain following peripheral nerve injury. Eur. J. Neurosci. 17, 1907–1920 (2003).
S. Tokunaga, Y. Takeda, K. Shinomiya, W. Yamamoto, Y. Utsu, K. Toide, C. Kamei, Changes of sleep patterns in rats with chronic constriction injury under aversive conditions. Biol. Pharm. Bull. 30, 2088–2090 (2007).
H. Bastuji, C. Perchet, V. Legrain, C. Montes, L. Garcia-Larrea, Laser evoked responses to painful stimulation persist during sleep and predict subsequent arousals. Pain 137, 589–599 (2008).
D. L. Tanelian, W. G. Brose, Neuropathic pain can be relieved by drugs that are use-dependent sodium channel blockers: Lidocaine, carbamazepine, and mexiletine. Anesthesiology 74, 949–951 (1991).
S. Haroutounian, L. Nikolajsen, T. F. Bendtsen, N. B. Finnerup, A. D. Kristensen, J. B. Hasselstrom, T. S. Jensen, Primary afferent input critical for maintaining spontaneous pain in peripheral neuropathy. Pain 155, 1272–1279 (2014).
A. Truini, L. Padua, A. Biasiotta, P. Caliandro, C. Pazzaglia, F. Galeotti, M. Inghilleri, G. Cruccu, Differential involvement of A-delta and A-beta fibres in neuropathic pain related to carpal tunnel syndrome. Pain 145, 105–109 (2009).
Q. Zheng, W. Xie, D. D. Luckemeyer, M. Lay, X. W. Wang, X. Dong, N. Limjunyawong, Y. Ye, F. Q. Zhou, J. A. Strong, J. M. Zhang, X. Dong, Synchronized cluster firing, a distinct form of sensory neuron activation, drives spontaneous pain. Neuron 110, 209–220.e6 (2022).
N. Agarwal, S. Offermanns, R. Kuner, Conditional gene deletion in primary nociceptive neurons of trigeminal ganglia and dorsal root ganglia. Genesis 38, 122–129 (2004).
L. Madisen, T. Mao, H. Koch, J. M. Zhuo, A. Berenyi, S. Fujisawa, Y. W. Hsu, A. J. Garcia III, X. Gu, S. Zanella, J. Kidney, H. Gu, Y. Mao, B. M. Hooks, E. S. Boyden, G. Buzsaki, J. M. Ramirez, A. R. Jones, K. Svoboda, X. Han, E. E. Turner, H. Zeng, A toolbox of Cre-dependent optogenetic transgenic mice for light-induced activation and silencing. Nat. Neurosci. 15, 793–802 (2012).
P. Franken, D. J. Dijk, I. Tobler, A. A. Borbely, Sleep deprivation in rats: Effects on EEG power spectra, vigilance states, and cortical temperature. Am. J. Physiol. 261, R198–R208 (1991).
I. Tobler, T. Deboer, M. Fischer, Sleep and sleep regulation in normal and prion protein-deficient mice. J. Neurosci. 17, 1869–1879 (1997).
H. Antila, I. Kwak, A. Choi, A. Pisciotti, I. Covarrubias, J. Baik, A. Eisch, K. Beier, S. Thomas, F. Weber, S. Chung, A noradrenergic-hypothalamic neural substrate for stress-induced sleep disturbances. Proc. Natl. Acad. Sci. U.S.A. 119, e2123528119 (2022).
I. Decosterd, C. J. Woolf, Spared nerve injury: An animal model of persistent peripheral neuropathic pain. Pain 87, 149–158 (2000).
C. Alexandre, A. Latremoliere, A. Ferreira, G. Miracca, M. Yamamoto, T. E. Scammell, C. J. Woolf, Decreased alertness due to sleep loss increases pain sensitivity in mice. Nat. Med. 23, 768–774 (2017).
S. Lecci, L. M. Fernandez, F. D. Weber, R. Cardis, J. Y. Chatton, J. Born, A. Luthi, Coordinated infraslow neural and cardiac oscillations mark fragility and offline periods in mammalian sleep. Sci. Adv. 3, e1602026 (2017).
G. J. Bennett, Y. K. Xie, A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 33, 87–107 (1988).
A. Latremoliere, A. Latini, N. Andrews, S. J. Cronin, M. Fujita, K. Gorska, R. Hovius, C. Romero, S. Chuaiphichai, M. Painter, G. Miracca, O. Babaniyi, A. P. Remor, K. Duong, P. Riva, L. B. Barrett, N. Ferreiros, A. Naylor, J. M. Penninger, I. Tegeder, J. Zhong, J. Blagg, K. M. Channon, K. Johnsson, M. Costigan, C. J. Woolf, Reduction of neuropathic and inflammatory pain through inhibition of the tetrahydrobiopterin pathway. Neuron 86, 1393–1406 (2015).
R. S. Ray, A. E. Corcoran, R. D. Brust, J. C. Kim, G. B. Richerson, E. Nattie, S. M. Dymecki, Impaired respiratory and body temperature control upon acute serotonergic neuron inhibition. Science 333, 637–642 (2011).
B. Abrahamsen, J. Zhao, C. O. Asante, C. M. Cendan, S. Marsh, J. P. Martinez-Barbera, M. A. Nassar, A. H. Dickenson, J. N. Wood, The cell and molecular basis of mechanical, cold, and inflammatory pain. Science 321, 702–705 (2008).
S. K. Mishra, S. M. Tisel, P. Orestes, S. K. Bhangoo, M. A. Hoon, TRPV1-lineage neurons are required for thermal sensation. EMBO J. 30, 582–593 (2011).
A. M. Binshtok, B. P. Bean, C. J. Woolf, Inhibition of nociceptors by TRPV1-mediated entry of impermeant sodium channel blockers. Nature 449, 607–610 (2007).
D. P. Roberson, A. M. Binshtok, F. Blasl, B. P. Bean, C. J. Woolf, Targeting of sodium channel blockers into nociceptors to produce long-duration analgesia: A systematic study and review. Br. J. Pharmacol. 164, 48–58 (2011).
R. H. Dworkin, M. Backonja, M. C. Rowbotham, R. R. Allen, C. R. Argoff, G. J. Bennett, M. C. Bushnell, J. T. Farrar, B. S. Galer, J. A. Haythornthwaite, D. J. Hewitt, J. D. Loeser, M. B. Max, M. Saltarelli, K. E. Schmader, C. Stein, D. Thompson, D. C. Turk, M. S. Wallace, L. R. Watkins, S. M. Weinstein, Advances in neuropathic pain: Diagnosis, mechanisms, and treatment recommendations. Arch. Neurol. 60, 1524–1534 (2003).
R. H. Dworkin, M. P. Jensen, A. R. Gammaitoni, D. O. Olaleye, B. S. Galer, Symptom profiles differ in patients with neuropathic versus non-neuropathic pain. J. Pain 8, 118–126 (2007).
M. M. Backonja, Use of anticonvulsants for treatment of neuropathic pain. Neurology 59, S14–S17 (2002).
C. Gauriau, J. F. Bernard, Pain pathways and parabrachial circuits in the rat. Exp. Physiol. 87, 251–258 (2002).
S. Kaur, J. L. Wang, L. Ferrari, S. Thankachan, D. Kroeger, A. Venner, M. Lazarus, A. Wellman, E. Arrigoni, P. M. Fuller, C. B. Saper, A genetically defined circuit for arousal from sleep during hypercapnia. Neuron 96, 1153–1167.e5 (2017).
C. A. Campos, A. J. Bowen, C. W. Roman, R. D. Palmiter, Encoding of danger by parabrachial CGRP neurons. Nature 555, 617–622 (2018).
F. Pan, G. Jones, Clinical perspective on pain and pain phenotypes in osteoarthritis. Curr. Rheumatol. Rep. 20, 79 (2018).
P. G. Conaghan, A. D. Cook, J. A. Hamilton, P. P. Tak, Therapeutic options for targeting inflammatory osteoarthritis pain. Nat. Rev. Rheumatol. 15, 355–363 (2019).
K. J. Burchiel, Carbamazepine inhibits spontaneous activity in experimental neuromas. Exp. Neurol. 102, 249–253 (1988).
P. J. Wiffen, S. Derry, R. A. Moore, E. A. Kalso, Topiramate for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst. Rev. 2013, CD005451 (2013).
H. Zhou, Q. Zhang, E. Martinez, J. Dale, S. Hu, E. Zhang, K. Liu, D. Huang, G. Yang, Z. Chen, J. Wang, Ketamine reduces aversion in rodent pain models by suppressing hyperactivity of the anterior cingulate cortex. Nat. Commun. 9, 3751 (2018).
S. E. Martin, H. M. Engleman, I. J. Deary, N. J. Douglas, The effect of sleep fragmentation on daytime function. Am. J. Respir. Crit. Care Med. 153, 1328–1332 (1996).
M. J. Reid, C. Climent-Sanz, P. H. Finan, The sleep-reward-pain pathway model: An integrative review. Curr. Sleep Med. Rep. 8, 97–104 (2022).
M. Devor, P. D. Wall, Type of sensory nerve fibre sprouting to form a neuroma. Nature 262, 705–708 (1976).
I. Tegeder, M. Costigan, R. S. Griffin, A. Abele, I. Belfer, H. Schmidt, C. Ehnert, J. Nejim, C. Marian, J. Scholz, T. Wu, A. Allchorne, L. Diatchenko, A. M. Binshtok, D. Goldman, J. Adolph, S. Sama, S. J. Atlas, W. A. Carlezon, A. Parsegian, J. Lotsch, R. B. Fillingim, W. Maixner, G. Geisslinger, M. B. Max, C. J. Woolf, GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence. Nat. Med. 12, 1269–1277 (2006).
S. J. F. Cronin, S. Rao, M. A. Tejada, B. L. Turnes, S. Licht-Mayer, T. Omura, C. Brenneis, E. Jacobs, L. Barrett, A. Latremoliere, N. Andrews, K. M. Channon, A. Latini, A. C. Arvanites, L. S. Davidow, M. Costigan, L. L. Rubin, J. M. Penninger, C. J. Woolf, Phenotypic drug screen uncovers the metabolic GCH1/BH4 pathway as key regulator of EGFR/ KRAS-mediated neuropathic pain and lung cancer. Sci. Transl. Med. 14, eabj1531 (2022).
M. Costigan, A. Moss, A. Latremoliere, C. Johnston, M. Verma-Gandhu, T. A. Herbert, L. Barrett, G. J. Brenner, D. Vardeh, C. J. Woolf, M. Fitzgerald, T-cell infiltration and signaling in the adult dorsal spinal cord is a major contributor to neuropathic pain-like hypersensitivity. J. Neurosci. 29, 14415–14422 (2009).
A. J. Davies, H. W. Kim, R. Gonzalez-Cano, J. Choi, S. K. Back, S. E. Roh, E. Johnson, M. Gabriac, M. S. Kim, J. Lee, J. E. Lee, Y. S. Kim, Y. C. Bae, S. J. Kim, K. M. Lee, H. S. Na, P. Riva, A. Latremoliere, S. Rinaldi, S. Ugolini, M. Costigan, S. B. Oh, Natural killer cells degenerate intact sensory afferents following nerve injury. Cell 176, 716–728.e18 (2019).
L. Vicuna, D. E. Strochlic, A. Latremoliere, K. K. Bali, M. Simonetti, D. Husainie, S. Prokosch, P. Riva, R. S. Griffin, C. Njoo, S. Gehrig, M. A. Mall, B. Arnold, M. Devor, C. J. Woolf, S. D. Liberles, M. Costigan, R. Kuner, The serine protease inhibitor SerpinA3N attenuates neuropathic pain by inhibiting T cell-derived leukocyte elastase. Nat. Med. 21, 518–523 (2015).
V. Kayser, F. Viguier, M. Ioannidi, J. F. Bernard, A. Latremoliere, B. Michot, J. M. Vela, H. Buschmann, M. Hamon, S. Bourgoin, Differential anti-neuropathic pain effects of tetrodotoxin in sciatic nerve- versus infraorbital nerve-ligated rats – Behavioral, pharmacological and immunohistochemical investigations. Neuropharmacology 58, 474–487 (2010).
J. Buritova, J. M. Besson, J. F. Bernard, Involvement of the spinoparabrachial pathway in inflammatory nociceptive processes: A c-Fos protein study in the awake rat. J. Comp. Neurol. 397, 10–28 (1998).
L. Sun, R. Liu, F. Guo, M. Q. Wen, X. L. Ma, K. Y. Li, H. Sun, C. L. Xu, Y. Y. Li, M. Y. Wu, Z. G. Zhu, X. J. Li, Y. Q. Yu, Z. Chen, X. Y. Li, S. Duan, Parabrachial nucleus circuit governs neuropathic pain-like behavior. Nat. Commun. 11, 5974 (2020).
S. Han, M. T. Soleiman, M. E. Soden, L. S. Zweifel, R. D. Palmiter, Elucidating an affective pain circuit that creates a threat memory. Cell 162, 363–374 (2015).
S. Choi, J. Hachisuka, M. A. Brett, A. R. Magee, Y. Omori, N. U. Iqbal, D. Zhang, M. M. DeLisle, R. L. Wolfson, L. Bai, C. Santiago, S. Gong, M. Goulding, N. Heintz, H. R. Koerber, S. E. Ross, D. D. Ginty, Parallel ascending spinal pathways for affective touch and pain. Nature 587, 258–263 (2020).
M. Devor, I. Wood, Y. Sharav, J. M. Zakrzewska, Trigeminal neuralgia during sleep. Pain Pract. 8, 263–268 (2008).
J. Mathes, J. Schuffelen, B. Dickmann, A. Gieselmann, R. Pietrowsky, Pain and nightmares—A diary study of patients with chronic pain. Dreaming 32, 183–193 (2022).
C. Alexandre, A. Latremoliere, P. H. Finan, in The Oxford Handbook of the Neurobiology of Pain, J. N. Wood, Ed. (Oxford University Press, 2020), pp. 557–608.
G. Vanini, Sleep deprivation and recovery sleep prior to a noxious inflammatory insult influence characteristics and duration of pain. Sleep 39, 133–142 (2016).
P. K. Wang, J. Cao, H. Wang, L. Liang, J. Zhang, B. M. Lutz, K. R. Shieh, A. Bekker, Y. X. Tao, Short-term sleep disturbance-induced stress does not affect basal pain perception, but does delay postsurgical pain recovery. J. Pain 16, 1186–1199 (2015).
K. Kourbanova, C. Alexandre, A. Latremoliere, Effect of sleep loss on pain-New conceptual and mechanistic avenues. Front. Neurosci. 16, 1009902 (2022).
P. Franken, A. Malafosse, M. Tafti, Genetic variation in EEG activity during sleep in inbred mice. Am. J. Physiol. 275, R1127–R1137 (1998).
M. J. Prerau, R. E. Brown, M. T. Bianchi, J. M. Ellenbogen, P. L. Purdon, Sleep neurophysiological dynamics through the lens of multitaper spectral analysis. Physiology 32, 60–92 (2017).
