Reduction of follistatin-like 1 in primary afferent neurons contributes to neuropathic pain hypersensitivity

Nerve injury-induced neuropathic pain is difficult to treat in clinic. Lack of comprehensive understanding of the mechanism underlying such chronic pain hypersensitivity delays the development of more effective therapy. Accumulated evidence shows that peripheral nerve injury alters the expression of many neurotransmitters, receptors, ion channels and signaling molecules in the dorsal root ganglion (DRG) and the dorsal horn of spinal cord ¹. Some of these molecular changes in the pain pathway are correlated with the current therapy for neuropathic pain. For example, the up-regulation of the α2δ1 subunit of voltage-gated Ca²⁺ channel, a target of analgesic gabapentin, in DRG neurons and the dorsal spinal cord could be a molecular basis for using gabapentin in neuropathic pain treatment ^{1, 2}. Down-regulated expression of μ-opioid receptors in DRG neurons partially explains the reduced effectiveness of morphine in neuropathic pain treatment ¹. We recently found that the nociceptive afferent transmission is suppressed by follistatin-like 1 (FSTL1), a member of the follistatin gene family ³. Furthermore, genetic deletion of FSTL1 in DRG neurons results in pain hypersensitivity ⁴.

Our present study shows that FSTL1 expression in rat DRG neurons is markedly decreased following peripheral nerve injury. To examine the nerve injury-induced changes in mRNA and protein levels of FSTL1, we prepared the spared nerve injury (SNI) model as described for rats ⁶. To confirm the effect of nerve damage on FSTL1 expression, we also prepared the sciatic nerve transection (SNT) model. The lumbar (L) 4 and L5 DRGs from rats (200 g, male) with unilateral SNI or SNT and control rats were processed for in situ hybridization. The number of FSTL1 mRNA-containing DRG neurons in the ipsilateral L4 and L5 DRGs was markedly reduced after peripheral nerve injury, as compared with that in the contralateral DRGs (Figure 1A; Supplementary information, Figure S1A). A similar number of FSTL1 mRNA-positive neurons was found in the contralateral DRGs and the DRGs of control rats. Thus, the expression of FSTL1 in DRG neurons is down-regulated after peripheral nerve injury.

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