Vagus nerve stimulation in awake rats reduces formalin-induced nociceptive behaviour and fos-immunoreactivity in trigeminal nucleus caudalis

Abstract

Besides its well-established efficacy in epilepsy, vagus nerve stimulation (VNS) may be of potential interest in pain treatment. It has, however, not yet been assessed in animal pain models with the devices and stimulation protocols used in humans. We have therefore studied in awake rats the effects of left cervical VNS on trigeminal nociception using an implantable electrode and stimulator (NCP-Cyberonics). VNS was applied for 24h at 2 mA intensity, 20 Hz frequency, 0.5 ms pulse width and a duty cycle of 20s ON/18s OFF. As a nociceptive stimulus, we injected formalin into the left mystacial vibrissae, assessed behaviour for 45 min and sacrificed the animals 45 min later. Fos-immunoreactive (Fos-Ir) neurons were counted in laminae I-II of trigeminal nucleus caudalis (TNC) on both sides. We used three groups of control animals: VNS without formalin, formalin without VNS and sham VNS (implanted without stimulation or formalin). Whereas sham VNS had no significant effect, VNS alone increased Fos expression in ipsilateral TNC in addition to the expected increase in nucleus tractus solitarius. It also significantly attenuated the increase of Fos-Ir neurons observed in ipsilateral TNC laminae I-II after formalin injection. If the proper VNS effect on Fos-expression was subtracted, the reduction of formalin-induced nociceptor activation was 55%. VNS also reduced nociceptive behaviour on average by 96.1% during the early phase (0-6 min) and by 60.7% during the late phase (6-45 min) after the formalin injection. These results suggest that VNS applied with a device used in human therapy may have in awake rats a significant antinociceptive effect in a model of trigeminal pain.

The Striatum and Pain Modulation

“…We recorded with microelectrodes the neuronal activity of the trigeminal nucleus caudalis (NC) in anaesthetized rats. This nucleus was elected because clinical (Green et al 2002;Morita and Hosobuchi 1992;Rosenkopf 1989), behavioral (Bohotin et al 2003;Duale et al 1996;Luccarini et al 1998;Rosenfeld et al 1983), anatomical (Clements et al 1991;Coimbra and Coimbra 1994;Strassman and Vos 1993;Voisin et al 2002), immunohistochemical (Strassman and Vos 1993;Bereiter et al 1994;Lu et al 1993;Meng and Bereiter 1996;Oakden and Boissonade 1998), and electrophysiological (Amano et al 1984;Carstens et al 1998;Chiang et al 1991;Dallel et al 1998;Hu et al 1981;Tsai et al 1999) evidence suggest that it is the most important site for relay of orofacial nociceptive information.…”

Convergence of cervical and trigeminal sensory afferents

“…Continuous vagal nerve stimulation (VNS) for 24 hours in awake rats produced significant antinociceptive effects in a model of trigeminal pain [64]. This showed that VNS stimulation significantly inhibits activation of second-order nociceptors in the TNC and pain-related behavior on the side of the facial nociceptive stimulus during the early and late phase.…”

Vagal afferent modulation of spinal trigeminal neuronal responses to dural electrical stimulation in rats

“…The analgesic effect of the vagal afferent stimulation has been reported in numerous behavioral pain tests in laboratory animals. For instance, the VNS-induced inhibition of the nociceptive digastric reflex induced by intense tooth-pulp stimulation (Maixner et al, 1991;Bossut et al, 1992), reduction of the cumulative duration of rubbing and scratching the injection site in the orofacial formalin test (Bohotin et al, 2003b), and latency increase of the tail-flick or the hind paw withdrawal response to noxious heat (Ren et al, 1989;Aicher et al, 1991;Thurston and Randich, 1991;Bohotin et al, 2003a) were reported. In epileptic patients treated with VNS, an increase in mechanical pain threshold was noted (Kirchner et al, 2000(Kirchner et al, , 2006.…”