Microglial activation in the trigeminal spinal subnucleus interpolaris/caudalis modulates orofacial incisional mechanical pain hypersensitivity associated with orofacial injury in infancy

Abstract

Infantile tissue injury induces sensory deficits in adulthood. Infantile facial incision (IFI) was reported to cause an enhancement of incision-induced mechanical hypersensitivity in adulthood due to acceleration of the trigeminal ganglion neuronal excitability. However, the effects of IFI on activation of microglia in the spinal trigeminal nucleus and its involvement in facial pain sensitivity is not well known. Methods: A facial skin incision was made in the left whisker pad in infant (IFI) and/or adult rats (AFI). Mechanical head withdrawal threshold and microglial activation in the trigeminal spinal nucleus were analyzed. Results: Mechanical pain hypersensitivity induced by AFI was significantly exacerbated and prolonged by IFI. The number of Iba1-immunoreactive cells in the trigeminal spinal nucleus following AFI was increased by IFI, suggesting that IFI facilitates microglial hyperactivation following AFI. Intraperitoneal administration of minocycline, a microglial activation inhibitor, suppressed the facial incision-induced microglial hyperactivation in the trigeminal spinal nucleus and the exacerbation of the facial mechanical pain hypersensitivity induced by IFI. Conclusion: These results suggest that facial trauma in infants causes hyperactivation of microglia in the trigeminal spinal nucleus following AFI, leading to the prolongation of the facial mechanical pain hypersensitivity.

Decreased PPARgamma in the trigeminal spinal subnucleus caudalis due to neonatal injury contributes to incision-induced mechanical allodynia in female rats

“…In contrast, in ltrated T cells in the spinal dorsal horn are reported to contribute to neuropathic pain in female animals 8,16 . In the Vc, we found that the prolonged incision-induced mechanical allodynia in male rats was dependent on microglia, which was consistent with a previous report 4 . Although CD3-positive cells were seen in the Vc after whisker pad skin reincision in both sexes, the number of CD3-positive cells was very small, suggesting that in ltrated T cells in the Vc are unlikely to be involved in prolonged incision-induced mechanical allodynia in female rats.…”

“…All rats were acclimated to the testing environment for 5 days. The von Frey laments (4,6,8,10,15,26,30,40,50,60, and 80 g) were applied to the left whisker pad skin according to the method described previously 41 . Each lament was used in an ascending manner.…”

“…We previously reported that microglial activation is required for the prolonged mechanical allodynia caused by whisker pad skin reincision in male rats that experienced an initial neonatal incision 4 . Given the involvement of microglia in pain signaling in the orofacial region of male rats, sex differences in pain signaling may be observed in the prolongation of skin incision-induced mechanical allodynia in adult rats with a previous neonatal incision.…”

“…Furthermore, nociceptive stimulation of the hind paw on postnatal day 3 changed the gene pro le in the spinal dorsal horn, which was maintained until adulthood 2 . Tissue injury in infancy also caused functional alterations in glial cells, such as microglia, in adulthood 3,4 . Activated microglia release brainderived neurotrophic factor (BDNF) which elicits the long-term potentiation of C-ber-mediated synaptic responses in the spinal dorsal horn, culminating in the maintenance of excessive neuronal activity 5 .…”

Decreased PPARgamma in the trigeminal spinal subnucleus caudalis due to neonatal injury contributes to incision-induced mechanical allodynia in female rats

“…Furthermore, nociceptive stimulation of the hind paw 3 days after birth changes the gene profile in the spinal dorsal horn, which was maintained until adulthood 2 . Functional alterations in glial cells such as microglia in adulthood were also caused by tissue injury in infancy 3 , 4 . After re-incision in the hind paw of the adult rats that experienced neonatal injury in the hind paw, microglia release brain-derived neurotrophic factor (BDNF) which elicits long-term potentiation of C-fiber-mediated synaptic responses in the spinal dorsal horn, culminating in the maintenance of excessive neuronal activity 5 .…”