Abstract
Although calcitonin gene-related peptide is a recognized pain transducer, the expression of calcitonin gene-related peptide in primary afferents may be differentially affected following different types of nerve injury. Here, we examined whether different calcitonin gene-related peptide expression patterns in primary afferents contributes to distinct sensory disturbances in three animal models of sciatic nerve injury: chronic constriction injury, mild (100 g force) or strong (1000 g force) transient crush in rats. Assessments of withdrawal reflexes and spontaneous behavior indicated that chronic constriction injury and mild crush resulted in positive neuropathic symptoms (static/dynamic mechanical allodynia, heat hyperalgesia, cold allodynia, spontaneous pain). However, strong crush led to both positive (dynamic mechanical allodynia, cold allodynia, spontaneous pain) and negative symptoms (static mechanical hypoesthesia, heat hypoalgesia). Calcitonin gene-related peptide immunoreactivity in dorsal root ganglia and corresponding spinal cord segments, and calcitonin gene-related peptide mRNA levels in dorsal root ganglia, indicated that the primary afferent calcitonin gene-related peptide supply was markedly reduced only after strong crush. This reduction paralleled the development of negative symptoms (static mechanical hypoesthesia and heat hypoalgesia). Administration of exogenous calcitonin gene-related peptide intrathecally after strong crush did not alter heat hypoalgesia but ameliorated static mechanical hypoesthesia, an effect blocked by a calcitonin gene-related peptide receptor antagonist. Thus, reducing the primary afferent calcitonin gene-related peptide supply contributed to subsequent negative neuropathic symptoms, especially to static mechanical stimuli. Moreover, nerve injury caused a subcellular redistribution of calcitonin gene-related peptide from small- and medium-size dorsal root ganglia neurons to large-size dorsal root ganglia neurons, which paralleled the development of positive neuropathic symptoms. Intrathecal administration of the calcitonin gene-related peptide receptor antagonist ameliorated these positive symptoms, indicating that the expression of calcitonin gene-related peptide in large-size dorsal root ganglia neurons is important for the positive neuropathic symptoms in all three models. Taken together, these results suggest that distinct calcitonin gene-related peptide expression pattern in primary afferents contribute to different neuropathic symptoms following chronic constriction or crush injuries to the rat sciatic nerve.