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BACKGROUND Sleep loss in infants may have a negative effect on the functional and structural development of the nociceptive system. We tested the hypothesis that neonatal sleep restriction induces a long-term increase of pain-related behaviors in mice and that this hypersensitivity occurs due to changes in the neuronal activity of nociceptive pathways. OBJECTIVES We aim to investigate the effects of sleep loss in neonatal mice on pain behaviors of adolescent and adult mice in a sex-dependent manner. We also analyzed neuroanatomical and functional changes in pain pathways associated with behavioral changes. STUDY DESIGN An experimental animal study. SETTING A basic sleep research laboratory at Universidade Federal de São Paulo in Brazil. METHODS Neonatal mice at postnatal day (PND) 12 were randomly assigned to either control (CTRL), maternal separation (MS), or sleep restriction (SR) groups. MS and SR were performed 2 hours a day for 10 days (PND 12 until PND 21). The gentle handling method was used to prevent sleep. At PND 21, PND 35, or PND 90, the mice were tested for pain-related behaviors. Their brains were harvested and immunohistochemically stained for c-Fos protein in the anterior cingulate cortex, primary somatosensory cortex, and periaqueductal gray (PAG). RESULTS Neonatal SR significantly increased nociceptive sensitivity in the hot plate test in adolescent mice (-23.5% of pain threshold). This alteration in nociceptive response was accompanied by a decrease in c-Fos expression in PAG (-40% of c-Fos positive cells compared to the CTRL group). The hypersensitivity found in adolescent mice was not present in adult animals, and all mice showed a comparable nociceptive response. LIMITATIONS Even using a mild manipulation method, in which a minimal amount of handling was applied to maintain wakefulness, sleep deprivation was a stressful event evidenced by higher corticosterone levels. CONCLUSION Repeated exposures to sleep loss during early life were able to induce changes in the nociceptive response associated with alterations in neural activity in descending control of pain. KEY WORDS Brain maturation, hypersensitivity, neuronal activity, nociception, pain, periaqueductal gray, postnatal development, sleep, sleep deprivation.