Reduced BDNF expression in the auditory cortex contributed to neonatal pain-induced hearing impairment and dendritic pruning deficiency in mice

Abstract

IntroductionProcedural pain in neonates is associated with impaired neurodevelopment. Whether hearing development is impaired, however, remains unknown. This study examined potential cause-and-effect relationship between neonatal pain and subsequent hearing loss in mice.MethodsMale C57BL/6J mouse pups received an intra-plantar injection of complete Freund’s adjuvant on postnatal day 7 or repetitive needle prick stimuli from postnatal days 0–7. Mechanical and thermal pain thresholds were tested between postnatal days 14 and 49. The auditory brainstem response test was used to determine hearing thresholds. The inner ear structures and dendritic morphology in auditory cortex were assessed using immunofluorescence and Golgi-staining. The effects of oxycodone, tropomyosin receptor kinase B agonists and antagonists were tested.ResultsNeonatal pain resulted in impaired hearing in adulthood of both pain models No damage or synapse loss was found in the cochlea but increased dendritic spine density and reduced brain-derived neurotrophic factor level were found in auditory cortex in neonatal pain group. Oxycodone attenuated hearing loss and the associated changes in dendritic spine density and brain-derived neurotrophic factor changes in auditory cortex. A tropomyosin receptor kinase B agonist reversed neonatal pain-induced hearing impairment and decreased caspase 3 expression in auditory cortex. Administration of tropomyosin receptor kinase B antagonist in naïve mouse pups impaired hearing development suppressed phosphorylated-AKT, and increased caspase 3 expression.ConclusionChronic pain during the neonatal period resulted in impaired hearing in adulthood in mice, possibly via the brain-derived neurotrophic factor signaling pathway and dendritic spine pruning deficiency in auditory cortex.

Exploring the bidirectional relationship between pain and mental disorders: a comprehensive Mendelian randomization study

“…Mental problems, in turn, may also increase pain perception by altering brain structures such as the hippocampal and hypothalamus [35]. At the molecular level, pain and psychological problems both occur through the sharing of abnormalities in multiple neurotransmitters, such as serotonin, substance P, dopamine, norepinephrine, γ-aminobutyric acid, and brain-derived neurotrophic factor [36][37][38]. Moreover, injury induced neuroinflammatory changes also play an important role in the pathophysiology of pain and psychological dysregulation, and an increasing number of studies [38,39] have focused on the roles of proinflammatory cytokines in physical and mental comorbidities.…”

Brain-Derived Neurotrophic Factor, Nociception and Pain

“…Injections of recombinant BDNF (into the ACC) or a viral vector synthesizing BDNF (into the ACC or S1) triggered an elevation of neuronal LTP and sustained pain hypersensitivity, which were abolished after blocking the trkB receptors. In a different study, CFA injection induced BDNF expression in astrocytes (and neurons but not microglia) in Au1 [76].…”

“…In another study, the BDNF/trkB-mediated signaling pathway in the rostral ACC was shown to be involved in the development of neuropathic spontaneous pain-related aversion upon activation of the N-methyl-d-aspartate (NMDA) NR2B receptors [75]. It has also very recently been reported that neonatal pain induced by intraplantar CFA injection or repetitive needle prick stimuli resulted in impaired hearing in adulthood associated with a decrease of BDNF immunoreactivity in neurons (and glia -see below) of the primary auditory cortex (Au1) in parallel with increased dendritic spine density, whilst no damage or synapse loss was found in the cochlea [76]. Oxycodone, a semi-synthetic opioid, attenuated hearing loss and alterations in Au1, and a trkB agonist reversed neonatal paininduced hearing impairment and decreased caspase 3 expression.…”