T-type calcium channel blocker Z944 restores cortical synchrony and thalamocortical connectivity in a rat model of neuropathic pain

Abstract

Oscillations are fundamental to communication between neuronal ensembles. We previously reported that pain in awake rats enhances synchrony in primary somatosensory cortex (S1) and attenuates coherence between S1 and ventral posterolateral (VPL) thalamus. Here, we asked whether similar changes occur in anesthetized rats and whether pain modulates phase-amplitude coupling between VPL and S1. We also hypothesized that the suppression of burst firing in VPL using Z944, a novel T-type calcium channel blocker, restores S1 synchrony and thalamocortical connectivity. Local field potentials were recorded from S1 and VPL in anesthetized rats 7 days after sciatic chronic constriction injury (CCI). In rats with CCI, low-frequency (4-12 Hz) synchrony in S1 was enhanced, whereas VPL-S1 coherence and theta-gamma phase-amplitude coupling were attenuated. Moreover, Granger causality showed decreased informational flow from VPL to S1. Systemic or intrathalamic delivery of Z944 to rats with CCI normalized these changes. Systemic Z944 also reversed thermal hyperalgesia and conditioned place preference. These data suggest that pain-induced cortical synchrony and thalamocortical disconnectivity are directly related to burst firing in VPL.

The Development of Nociceptive Network Activity in the Somatosensory Cortex of Freely Moving Rat Pups

“…Gamma coherence has been associated with inter-regional communication within the brain, otherwise known as communication through coherence (Buzsáki and Draguhn 2004), but since the neural origins of the gamma oscillations recorded here is not known, the proposal that increases in gamma energy signals the beginning of long distance communications in pain networks should be viewed with caution (Buzsáki and Schomburg 2015). An increase in theta energy has been reported in awake adult rat somatosensory cortex following both capsaicin application to the skin and chronic nerve injury (LeBlanc et al 2014, 2016b) and also after noxious thermal skin stimulation in anaesthetized adult rats (Devonshire et al 2015). Theta and gamma energy, if comparable to human EEG data, could reflect the maturation of sensorimotor transformation of pain (Schulz et al 2012) or increased attentional processing and enhanced saliency of pain-related signals (Hauck et al 2007) as well as subjective pain intensity (Zhang et al 2012; Dufort Rouleau et al 2015).…”

Thalamic Bursts and the Epic Pain Model

“…However, conflicting evidence suggests thalamic bursts may be positively (Lenz et al, 1989; Llinás et al, 1999; Hains et al, 2005, 2006; Iwata et al, 2011; Leblanc et al, 2016b) or negatively (Radhakrishnan et al, 1999; Kim et al, 2003; Cheong et al, 2008; Huh et al, 2012; Huh and Cho, 2013) correlated with pain. While tonic firing in wake monkeys follows a linear stimulus-response function, suggesting rate coding properties (Bushnell et al, 1993), thalamic bursts have been argued to signal changes in the environment to cortex more effectively than tonic firing (Swadlow and Gusev, 2001).…”

Heantos-4, a natural plant extract used in the treatment of drug addiction, modulates T-type calcium channels and thalamocortical burst-firing

“…Pan T-type blockers that block burst-firing in both VB [18] and TRN [31] neurons have been shown to suppress seizures in animal models of absence epilepsy [31, 58], prevent seizure kindling in a model of complex-partial seizures [59], and suppress tonic-clonic seizures [60]. In terms of pain signalling, pan T-type antagonists have shown efficacy in reducing pain sensation in both animal models [54, 61–63] and humans [64, 65]. T-type calcium currents underlying burst-firing and slow oscillations in the thalamocortical system have been extensively linked to non-REM sleep [6].…”