Dermatomal scratching after intramedullary quisqualate injection: correlation with cutaneous denervation.

Traumatic and/or ischemic spinal cord injury (SCI) causes local cell death and dysfunction from the primary insult and from initiation of excitotoxic and inflammatory cascades.4,10,24 SCI often causes sensory, autonomic, and motor dysfunction and loss, including at-level and below-level pain.8,38,40 Historically, SCI research has focused on the injury epicenter and adjacent tissue. Recent efforts to understand the full impact of SCI have led to studies focusing on remote sites, including cortical and subcortical regions of the brain.1,5,19 Potential effects of SCI on peripheral sensory function and tissues are not as well-characterized. Because primary afferents extend 1 of their 2 axons into the spinal cord, we investigated whether dorsal horn injury might have peripheral consequences that contribute to functional/behavioral sensory changes. A secondary goal of this study was to further investigate the anatomical substrate for dermatomal scratching after SCI. Intramedullary injection of quisqualate (QUIS) results in spontaneous biting and scratching behavior at the dermatome associated with the level of injury. This “overgrooming” or “excessive grooming” is associated with loss of neurons in the deep dorsal horn while sparing neurons in the superficial lamina.36 Elimination of neurons in this region that express NK-1 receptors prevents or eliminates excessive grooming behavior.39 Although traditionally interpreted as a manifestation of spontaneous pain,36 a recent alternative hypothesis is that overgrooming may reflect uncontrolled scratching of neuropathic itch.9 The rationale for this proposal is that patients with neuropathic pain usually shield their affected area from contact, which can be painful (allodynia), whereas patients with neuropathic scratching report that their motivation is itch, not pain.22 Patients whose neuropathic itch has led to self-injury from their scratching (like QUIS-injected rats), report that loss of pain sensation from their injury removes the natural protection that limits scratching.21 A human correlate of overgrooming in QUIS-injected rats—dermatomal itching and scratching—has been proposed in patients with SCI from intramedullary cavernous hemangiomas.9,33,41 This has been suggested to represent central itch, since these hemangiomas were intramedullary. Hemosiderin and gliosis were posited to trigger ectopic activity of second-order itch projection neurons in dorsal horn lamina I.2 The current study examines an alternative hypothesis that QUIS injection may cause damage to at-level peripheral nerves. We evaluated whether there were peripheral axonal correlates of QUIS overgrooming using computerized stereological methods to estimate total length of PGP9.5-IR axons within the epidermis. We compared skin sampled from unoperated rats and rats that did or did not overgroom after QUIS injections. More than 90% of such epidermal neurites are TRPV1-IR nociceptors.29 Additionally, the presence of activating transcription factor-3 (ATF-3) immunoreactivity in at-level dorsal root ganglia neuronal cell bodies was assessed to determine if cutaneous neurite loss after QUIS injection represents central-distal peripheral axonopathy31 or death of entire primary afferent fibers. The results suggest that intramedullary QUIS injection, a model of SCI, causes profound peripheral nervous system (PNS) as well as central nervous system (CNS) injury, and that development of post-QUIS dermatomal overgrooming, currently used as a marker of central pain, may in addition represent neuropathic itch in profoundly denervated skin.