The reduction of intraepidermal P2X3 nerve fiber density correlates with behavioral hyperalgesia in a rat model of nerve injury‐induced pain

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Neuropathic pain is a syndrome caused by a lesion or disease of the somatosensory nervous system, most commonly peripheral neuropathy. In the latter, damage to nociceptors, that is, thinly myelinated (Aδ) or unmyeliniated (C) primary afferent nerve fibers, presumably is the initiating event, since at least clinically selective degeneration of Aβ fibers (e.g., in vitamin B12 deficiency [Koike et al., 2015], cis‐platinum induced peripheral neuropathy [Jongen, Broijl, & Sonneveld, 2015] or Friedreich's ataxia [Durr et al., 1996]) causes significant neuropathic pain in only a minority of patients, while on the other hand selective small‐fiber neuropathies (e.g., in sarcoidosis, HIV, amyloidosis, and Fabry's disease) (Hoeijmakers, Faber, Lauria, Merkies, & Waxman, 2012) are almost invariably painful. Once neuropathic pain has been initiated by damage to nociceptors, it is maintained by adaptive changes in other parts of the sensory system, like increased spontaneous activity of un‐injured Aδ and C fibers (Hulse, Wynick, & Donaldson, 2010), increased spontaneous activity of Aβ fibers (Govrin‐Lippmann & Devor, 1978), sprouting of autonomic nerve fibers in the upper dermis (Grelik, Bennett, & Ribeiro‐da‐Silva, 2005; Taylor, Osikowicz, & Ribeiro‐da‐Silva, 2012), expression changes in the dorsal root ganglion (Villar et al., 1991; Michael, Averill, Shortland, Yan, & Priestley, 1999; Li, Song, Higuera, & Luo, 2004; Chen et al., 2014) and changes in the spinal cord and brainstem (West, Bannister, Dickenson, & Bennett, 2015).
Skin biopsies, using immunohistochemistry with the pan neuronal marker PGP9.5 (Wang, Hilliges, Jernberg, Wiegleb‐Edstrom, & Johansson, 1990), provide an accessible way to study changes in innervation following nerve injury (Lauria et al., 2010). While Aβ fibers terminate in specialized end‐organs in the dermis (Nolano et al., 2003), Aδ and C nociceptors terminate as fine unmyelinated nerve fibers, so‐called free nerve endings (Cauna, 1980), in the epidermis. C‐fibers, which make‐up the majority of nociceptors, can be broadly subdivided into two classes: peptidergic nerve fibers, which contain neuropeptides like calcitonin gene‐related peptide (CGRP), and non‐peptidergic nerve fibers, which can be identified by expression of the P2X3 receptor (Bradbury, Burnstock, & McMahon, 1998; Burnstock, 2000; Taylor, Peleshok, & Ribeiro‐da‐Silva, 2009), a ligand gated ion‐channel which is responsive to adenosine triphosphate.
The epidermis is predominantly innervated by non‐peptidergic nociceptors (Perry & Lawson, 1998), while the internal organs receive mostly peptidergic innervation (Plenderleith & Snow, 1993; Perry & Lawson, 1998; Taylor et al., 2009; Guedon et al., 2016) or peptidergic and non‐peptidergic innervation to an equal degree (Bradbury et al., 1998). At the same time, sensory qualities that are distinct in neuropathic pain, like paresthesias, burning pain and tactile allodynia, are typically experienced in skin, suggesting an important role for the non‐peptidergic subclass of nociceptors in neuropathic pain. No consistent correlation between severity of neuropathic pain (behavior) and (intra)epidermal nerve fiber density (IENFD) exists (Lindenlaub & Sommer, 2002; Kalliomaki et al., 2011; Schley et al., 2012). We hypothesize that neuropathic pain may be initiated and/or maintained by selective degeneration of non‐peptidergic subclass of primary afferent nerve fibers.
To test this hypothesis, varying degrees of neuropathy were induced by partial ligation of the proximal sciatic nerve in a rat. This model, which was first described by Seltzer et al., induces hyperalgesia in the rat footpad with various levels of intensity. These levels are uniform but graded, depending on the proportion of sciatic nerve fibers contained within the ligation (Seltzer, Dubner, & Shir, 1990). We set out to study correlations between epidermal innervation in skin biopsies from the footpad and mechanical and thermal hyperalgesia in that same area, using PGP9.5, CGRP, and P2X3 immunohistochemistry.
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