Bilateral tactile hypersensitivity and neuroimmune responses after spared nerve injury in mice lacking vasoactive intestinal peptide

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Abstract

Vasoactive intestinal peptide (VIP) is one of the neuropeptides showing the strongest up-regulation in the nociceptive pathway after peripheral nerve injury and has been proposed to support neuropathic pain. Nevertheless, the story may be more complicated considering the known suppressive effects of the peptide on the immune reactivity of microglial cells, which have been heavily implicated in the onset and maintenance of pain after nerve injury. We here used mice deficient in VIP and the model of spared nerve injury, characterized by persistent tactile hypersensitivity. While tactile hypersensitivity developed similarly to wild type mice for the ipsilateral hindpaw, only transgenic mice showed a mirror-image tactile hypersensitivity in the contralateral hindpaw. This exacerbated neuropathic pain phenotype appeared to be mediated through a local mechanism acting at the level of the lumbar spinal cord as a distant nerve lesion in the front limb did not lead to hindpaw hypersensitivity in VIP-deficient mice. Innocuous tactile hindpaw stimulation was found to increase a neuronal activation marker in the bilateral superficial laminae of the lumbar dorsal horn of VIP-deficient, but not wild type mice, after SNI. A deeper study into the immune responsiveness to the nerve lesion also proved that VIP-deficient mice had a stronger early pro-inflammatory cytokine response and a more pronounced microglial reactivity compared to wild type controls. The latter was also observed at four weeks after spared nerve injury, a time at which bilateral tactile hypersensitivity persisted in VIP-deficient mice. These data suggest an action of VIP in neuropathic states that is more complicated than previously assumed. Future research is now needed for a deeper understanding of the relative contribution of receptors and fiber populations involved in the VIP-neuropathic pain link.

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