Neonatal anoxia increases nociceptive response in rats: Sex differences and lumbar spinal cord and insula alterations

Abstract

Neonatal anoxia is a well-known world health problem that results in neurodevelopmental deficits, such as sensory alterations that are observed in patients with cerebral palsy and autism disorder, for which oxygen deprivation is a risk factor. Nociceptive response, as part of the sensory system, has been reported as altered in these patients. To determine whether neonatal oxygen deprivation alters nociceptive sensitivity and promotes medium-and long-term inflammatory feedback in the central nervous system, Wistar rats of around 30 h old were submitted to anoxia (100% nitrogen flux for 25 min) and evaluated on PND23 (postpartum day) and PND90. The nociceptive response was assessed by mechanical, thermal, and tactile tests in the early postnatal and adulthood periods. The lumbar spinal cord (SC, L4-L6) motor neurons (MNs) and the posterior insular cortex neurons were counted and compared with their respective controls after anoxia. In addition, we evaluated the possible effect of anoxia on the expression of astrocytes in the SC at adulthood. The results showed increased nociceptive responses in both males and females submitted to anoxia, although these responses were different according to the nociceptive stimulus. A decrease in MNs in adult anoxiated females and an upregulation of GFAP expression in the SC were observed. In the insular cortex, a decrease in the number of cells of anoxiated males was observed in the neonatal period. Our findings suggest that oxygen-deprived nervous systems in rats may affect their response at the sensorimotor pathways and respective controlling centers with sex differences, which were related to the used stimulus.

Neonatal Anoxia Impacts Rats’ Maternal Behavior and Offspring Development due to Ultrasonic Vocalization’s Impairment

“…Despite this knowledge, assessing sex differences in basic neuroscience and preclinical studies is relatively scarce. Previous research in our laboratory evaluated Wistar rats, considering sex differences, the ontogeny of reflexes onset, the sensorimotor development [7, 13, 14], and allodynia sensibility [16]. Nevertheless, it might be necessary not only to focus on the changes that emerge at a given chronological age across groups but to examine whether those changes emerge earlier or later as a function of the quantity or quality of mother-infant interactions [17, 18, 22, 43, 83, 84].…”

“…Our model opted to expose the pups at postpartum day 2 (P2) because it resembles the developmental stage of a 25-27-week gestation (preterm infant) [9][10][11][12]. We observed sex differences in the ontogeny of reflexes and development [7,[13][14][15] and interesting outcomes of NA in pain perception, insular damage, and increased astrocitary response [16]. Other models such as Rice-Vannucci of hypoxia-ischemia [9], hypoxia only, and preterm inflammatory have their value and are magnificently reviewed in Millar et al [1].…”

Sex-specific developmental changes in spinal cord pain pathways following neonatal inflammation

“…Similarly, the impact of neonatal anoxia on sensorimotor processing demonstrated increased GFAP, as measured by western blot, in the spinal cord of adult female rats exposed to neonatal anoxia. Importantly, this aligned with a decrease in mechanical and thermal thresholds for paw withdrawal (Helou et al, 2021).…”

Enhanced nociceptive behavior and expansion of associated primary afferents in a rabbit model of cerebral palsy

“…We would be remiss if we did not also postulate that perinatal HI may also induce anatomical and physiological plasticity of other subtypes of primary afferent fibers or supraspinal centers involved in pain perception or pain modulation. Anoxia in the neonatal rat has been shown to lead to paw hypersensitivity and significantly fewer cells in the ventroposterolateral nucleus of the thalamus and somatosensory and insular cortex (Helou et al, 2021; Kumar et al, 2020, 2017).…”