Fos‐enkephalin signaling in the rat medial vestibular nucleus facilitates vestibular compensation

Abstract

In the present study, we first observed up-regulation in preproenkephalin (PPE)-like immunoreactivity (-LIR), a precursor of Met- and Leu-enkephalin, in the rat ipsilateral medial vestibular nucleus (ipsi-MVN) after unilateral labyrinthectomy (UL). By means of double-staining immunohistochemistry with PPE and Fos, a putative regulator of PPE gene expression, we revealed that some of these PPE-LIR neurons were also Fos immunopositive. The time course of decay of these double-stained neurons was quite parallel to that of UL-induced behavioral deficits. This suggests that these double-labeled neurons could have something to do with development of vestibular compensation. We next examined correlation between Fos and PPE expression in the ipsi-MVN by means of a 15-min pre-UL application of antisense oligonucleotide probes against c-fos mRNA into the ipsi-MVN. Gel shift assay and Western blotting revealed that elimination of Fos expression significantly reduced both AP-1 DNA binding activity and PPE expression in the ipsi-MVN after UL. C-fos antisense study also revealed that depression of Fos-PPE signaling in the ipsi-MVN caused significantly more severe behavioral deficits during vestibular compensation. Furthermore, studies with PPE antisense and naloxone, an opioid receptor antagonist, demonstrated that specific depression of enkephalinergic effects in the ipsi-MVN significantly delayed vestibular compensation. All these findings suggest that, immediately after UL, Fos induced in some of the ipsi-MVN neurons could regulate consequent PPE expression via the AP-1 activation and facilitate the restoration of balance between bilateral MVN activities via the opioid receptor activation, resulting in progress of vestibular compensation.

Activation of μ-opioid receptors inhibits calcium-currents in the vestibular afferent neurons of the rat through a cAMP dependent mechanism

“…In addition, in the vestibular compensation produced after an unilateral labyrentectomy, the inhibition of the I Ca may contribute to vestibular plasticity through the modulation of gene expression (Kitahara et al, 2006; Catterall, 2011; Beraneck and Idoux, 2012). The accuracy of the vestibular system critically depends on the balance between the gains of both vestibules (Sadeghi et al, 2009; Cullen, 2012).…”

“…Recordings in slices obtained from the medial vestibular nucleus (MVN) of the rat have shown that delta-opioid receptor agonists decreased the neuronal tonic discharge (Sulaiman and Dutia, 1998). Further, the use of preproenkephalin antisense and naloxone significantly delayed vestibular compensation (Kitahara et al, 2006). …”

Endogenous opiates and behavior: 2009

“…Unilateral labyrinthectomy causing vestibular behavioral deficits was accompanied by pre-pro-Enk up regulation and increased Fos activity in the medial vestibular nucleus. Blockade of this up regulation with naloxone or antisense probes increased the behavioral deficits (590). DYN anti-sera applied soon after spinal cord ischemia attenuated NOS up-regulation, and reduced both spinal edema and cell injury (1022).…”

Fos Expression in the Rat Vestibular Nucleus Complex after Plugging the Three Semicircular Canals

“…On the other hand, as fos can form heterodimeric AP-1 complexes binding to AP-1 sites on different gene promoters, it can upregulate preproenkephalin mRNA, a precursor of Met- and Leu-enkephalin in ipsilateral MVNs after UL, for the preproenkephalin gene has a DNA binding site (AP-1) in its promoter region [21, 22]. It was said that this Fos-preproenkephalin signaling in the ipsilateral MVNs could be effective mainly at the chronic stage rather than at the very early stage.…”