Person:

Lee, Jeungchan

Central nervous system lesions cause peripheral dysfunctions currently attributed to central cell death that compromises function of intact peripheral nerves. Injecting quisqualate (QUIS) into the rat spinal cord models spinal cord injury (SCI) and causes at-level scratching and self-injury. Such overgrooming was interpreted to model pain until patients with self-injurious scratching after SCI reported itch motivated scratching that was painless because of sensory loss. Because self- injurious scratching is difficult to explain by central mechanisms alone, we hypothesized that QUIS injections damage peripheral axons of at-level afferents. QUIS was injected into thoracic spinal cords of 18 Long-Evans rats. Animals were killed 3 days after overgrooming began or 14 days after injection. Spinal cord lesions were localized and DRG-immunolabeled for ATF-3. At- level and control skin samples were PGP9.5-immunabeled to quantify axons. Eighty-four percent of QUIS rats overgroomed. Skin in these regions had lost two-thirds of epidermal innervation as compared with controls (P < .001). Rats that overgroomed had 47% less axon-length than nongrooming rats (P = .006). The presence of ATF-3 immunolabeled neurons within diagnosis- related groups of QUIS rats indicated death of afferent cell bodies. Overgrooming after QUIS injections may not be due entirely to central changes. As in humans, self-injurious neuropathic scratching appeared to require loss of protective pain sensations in addition to peripheral denervation.

BACKGROUND: Complex Regional Pain Syndrome (CRPS)-I consists of chronic limb pain and dysautonomia triggered by traumas that sometime seem too trivial to be causative. Several pathological studies have identified minor distal nerve injuries (DNIs) in CRPS-I patients, but retrospective studies cannot establish causality. Therefore, we, prospectively investigated whether DNIs are sufficient to cause CRPS-like abnormalities in animals. We used needlestick, a cause of human CRPS, to evaluate lesion-size effects.

METHODS: Left tibial nerves of male Sprague–Dawley rats were transfixed once by 30G, 22G, or 18G needles. Unoperated and sham-operated rats provided controls. Hindpaw sensory function, edema, and posture were measured.

RESULTS: At Day-7 postoperatively, thresholds for ipsilateral-hindpaw withdrawal from Semmes–Weinstein monofilaments were reduced by ≥51% in 0% of sham-operated controls; 67% of rats that received 18G-DNI, 88% that received 22G-DNI, and 89% that received 30G-DNI. Fifty-seven percent of all DNI rats had contralateral hindpaw “mirror” changes. The prevalence and severity of allodynia appeared independent of lesion size. Hyperalgesic responses to cold and pinprick applied to the plantar hindpaw were less common and were ipsilesional only, as was neurogenic hindpaw edema. Ipsilesional-only, tonic, dystonic-like hindpaw postures were evident in 42% of 18G-DNI, 6% of 22G-DNI, and no 30G-DNI or sham-operated control rats. The prevalence of postural abnormalities correlated with needle diameter (P = 0.001). Counting protein gene product 9.5-immunolabeled axons in skin biopsies from rats’ ipsilesional hindpaws demonstrated mean reductions of 0% after 30G-needlestick, 15% after 22G-needlestick, and 26% after 18G-needlestick, which closely reproduces the 29% mean epidermal neurite losses of CRPS-I patients.

CONCLUSIONS: Needlestick DNI models several clinical and pathological features of human CRPS and provides direct prospective evidence that even minor DNI can cause CRPS-like abnormalities in rats.