Spinal TNFα is necessary for inactivity-induced phrenic motor facilitation

A prolonged reduction in central neural respiratory activity elicits a form of plasticity known as inactivity-induced phrenic motor facilitation (iPMF), a rebound' increase in phrenic burst amplitude apparent once respiratory neural activity is restored. iPMF requires atypical protein kinase C (aPKC) activity within spinal segments containing the phrenic motor nucleus to stabilize an early transient increase in phrenic burst amplitude and to form long-lasting iPMF following reduced respiratory neural activity. Upstream signal(s) leading to spinal aPKC activation are unknown. We tested the hypothesis that spinal tumour necrosis factor- (TNF) is necessary for iPMF via an aPKC-dependent mechanism. Anaesthetized, ventilated rats were exposed to a 30 min neural apnoea; upon resumption of respiratory neural activity, a prolonged increase in phrenic burst amplitude (42 +/- 9% baseline; P < 0.05) was apparent, indicating long-lasting iPMF. Pretreatment with recombinant human soluble TNF receptor 1 (sTNFR1) in the intrathecal space at the level of the phrenic motor nucleus prior to neural apnoea blocked long-lasting iPMF (2 +/- 8% baseline; P > 0.05). Intrathecal TNF without neural apnoea was sufficient to elicit long-lasting phrenic motor facilitation (pMF; 62 +/- 7% baseline; P < 0.05). Similar to iPMF, TNF-induced pMF required spinal aPKC activity, as intrathecal delivery of a -pseudosubstrate inhibitory peptide (PKC-PS) 35 min following intrathecal TNF arrested TNF-induced pMF (28 +/- 8% baseline; P < 0.05). These data demonstrate that: (1) spinal TNF is necessary for iPMF; and (2) spinal TNF is sufficient to elicit pMF via a similar aPKC-dependent mechanism. These data are consistent with the hypothesis that reduced respiratory neural activity elicits iPMF via a TNF-dependent increase in spinal aPKC activity.