VGF (nonacronymic) is a granin-like protein that is packaged and proteolytically processed within the regulated secretory pathway. VGF and peptides derived from its processing have been implicated in neuroplasticity associated with learning, memory, depression, and chronic pain. In sensory neurons, VGF is rapidly increased following peripheral nerve injury and inflammation. Several bioactive peptides generated from the C-terminus of VGF have pronociceptive spinal effects. The goal of the present study was to examine the spinal effects of the peptide TLQP-21 and determine whether it participates in spinal mechanisms of persistent pain. Application of exogenous TLQP-21 induced dose-dependent thermal hyperalgesia in the warm-water immersion tail-withdrawal test. This hyperalgesia was inhibited by a p38 mitogen-activated protein kinase inhibitor, as well as inhibitors of cyclooxygenase and lipoxygenase. We used immunoneutralization of TLQP-21 to determine the function of the endogenous peptide in mechanisms underlying persistent pain. In mice injected intradermally with complete Freund adjuvant, intrathecal treatment with anti-TLQP-21 immediately prior to or 5 hours after induction of inflammation dose-dependently inhibited tactile hypersensitivity and thermal hyperalgesia. Intrathecal anti-TL21 administration also attenuated the development and maintenance of tactile hypersensitivity in the spared nerve injury model of neuropathic pain. These results provide evidence that endogenous TLQP-21 peptide contributes to the mechanisms of spinal neuroplasticity after inflammation and nerve injury.
Bibliographical noteFunding Information:
The authors would like to thank Galina Kalyuzhnaya for technical assistance, and Drs. Christopher N. Honda, George Wilcox, and Robert Elde for valuable insights. Grant Support: R01 DE021996 (L.V. and S.R.S.), T32 RR018719 (J.A.D.), RO1 MH086499 (S.R.S.), R33 MH083496 (S.R.S.), Diabetes Action Research and Education Foundation (S.R.S.), NARSAD van Ameringen Investigator Award (S.R.S.), Hope for Depression Research Foundation (SRS).
- Neuropathic pain