Hypothalamic A 11 Nuclei Regulate the Circadian 2 Rhythm of the Mechanonociception and the Spinal 3 Clock Gene Transcription through Dopamine 4 Receptor Activation 5

Patients with degenerative diseases refer to feeling more pain during the 21 night. However, it is unknown whether spinal nociception can be circadian and 22 how is it controlled. We investigated whether the paw withdrawal threshold (PWT) 23 could exhibit physiological circadian behavior as well as the contribution of the 24 dopaminergic A11 nucleus and the spinal dopamine (DA) receptors (DRs) on the 25 circadian PWT and the spinal clock gene transcription. Results revealed that control 26 rats present a circadian PWT. Injecting 6-hydroxidopamine (6-OHDA) into the 27 dopaminergic A11 nucleus reduced DA tissue content in the lumbar spinal cord, 28 abolished the circadian PWT, induced allodynia, and reduced Period 1 and 2 (Per1 29 and 2), retinoid-related orphan receptor α (Rorα), Cryptochrome 1 (Cry1), and 30 brain and muscle aryl-hydrocarbon receptor nuclear translocator-like protein 31 (Bmal) mRNA. Likewise, administration of D1-like and D2-like DR antagonists 32 blunted circadian PWT, producing allodynia, and altered the clock genes mRNA. 33 In contrast, administration of D1-like or D2-like DR agonists blocked 6-OHDA34 induced allodynia. This study shows that the spinal cord has physiological 35 circadian PWT, which is modulated by the descending dopaminergic A11 through 36 differential activation of the spinal DRs. Also, A11 nuclei and spinal DRs can 37 regulate the clock gene transcription, which can likely modulate the circadian PWT. 38