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A spinal analog of memory reconsolidation enables reversal of hyperalgesia

Abstract

Hyperalgesia arising from sensitization of pain relays in the spinal dorsal horn shares many mechanistic and phenotypic parallels with memory formation. We discovered that mechanical hyperalgesia could be rendered labile and reversible in mice after reactivation of spinal pain pathways in a process analogous to memory reconsolidation. These findings reveal a previously unknown regulatory mechanism underlying hyperalgesia and demonstrate the existence of reconsolidation-like processes in a sensory system.

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Figure 1: Reactivation of sensitized pain pathways renders hyperalgesia labile and reversible.
Figure 2: Requirement of glutamate, substance P, CaMKII and ERK signaling to render hyperalgesia labile.
Figure 3: LTP in SDH rendered labile after repeated stimulation.

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Acknowledgements

We thank M. Desrochers-Couture and L.J. Martin for their assistance and advice with the behavioral assays. This work was supported by a Pfizer–Fonds de recherche Québec–Santé (FRQS) Innovation Fund Award to Y.D.K., an FRQS post-doctoral Fellowship to R.P.B., Canadian Institutes of Health Research grant MOP 12942 to Y.D.K., and the Catherine Bushnell Pain Research Fellowship from the Louise and Alan Edwards foundation to R.P.B.

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R.P.B. conducted all of the experiments and analyses. R.P.B. and Y.D.K. designed the experiments and wrote the manuscript.

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Correspondence to Yves De Koninck.

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The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Labile plasticity in spinal pain pathways enables reversal of hyperalgesia

(a) Intrathecal injection of anisomycin (Aniso) immediately prior to a single intraplantar injection of capsaicin (Cap) prevents the development of mechanical hyperalgesia 3 h after injection (Post-Cap). n = 6 mice per group. (b) Changes in mechanical withdrawal thresholds induced by intraplantar injection of capsaicin (t = 0 h) followed by a second ipsilateral intraplantar injection of Cap (t = 3 h). The intrathecal (i.t.) injection of Aniso or Veh at 2h15 ± 5 min after the second Cap injection did not alter hyperalgesia. (c) Changes in mechanical withdrawal thresholds induced by intraplantar injection of capsaicin (t = 0 h) followed by a second ipsilateral intraplantar injection of Cap or Veh and intraperitoneal (i.p.) injection of Aniso or Veh (t = 3 h). n = 6 mice per group except Veh + Aniso n = 5. (d) Summary of antihyperalgesia induced by the treatments in (c), expressed as percentage of maximum possible effect (MPE). (e) Changes in mechanical withdrawal thresholds induced by intraplantar injection of Cap (t = 0 h) followed by a second ipsilateral intraplantar injection of Cap or Veh and intrathecal (i.t.) injection of cycloheximide (CHX; t = 3 h). MPE: CHX + Veh = 25.7% ± 9.0%; CHX + Cap = 80.2% ± 22.0%; P = 0.045; n = 6 mice per group. (f) Low frequency (2 Hz) optical stimulation of a hind paw for 20 min in anesthetized Nav1.8+-ChR2 mice induces a transient mechanical hyperalgesia. Data shown as difference in withdraw threshold between stimulated (stim) and unstimulated (control) paw. *** indicates P < 0.001 at 1 h. n = 12 mice per group. (g) Plot of minimum intensity of light required to induce paw withdrawal from 488 nm light by Nav1.8+-ChR2 mice receiving intraplantar injection of Cap (t = 0 h) followed by light-induced sensitization (2 Hz, 20 min; Light) or sham stimulation (Sham) and intrathecal injection of Aniso or Veh (t = 3 h). n = 6 mice per group. (hj) Capsaicin-induced hyperalgesia followed by intrathecal injection of: (h) AMPA ± Aniso, (i) NMDA ± Aniso, (j) Sar9,Met(O2)11-Substance P (SP) ± Aniso. (k) Summary of results from (h–j) expressed as MPE. n = 6 mice per group, except SP + Aniso: n = 5 mice, AMPA + Aniso: n = 12 mice. (l) Long term potentiation of post-synaptic field potentials (fPSPs) in the superficial dorsal horn induced by 2 Hz electrical stimulation (black arrow). n = 12 and 10 experiments from 6 and 5 mice in Control and APV, respectively. *, **, *** indicates P < 0.05, P < 0.01, and P < 0.001, respectively. All data are mean ± s.e.m. Source data

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Bonin, R., De Koninck, Y. A spinal analog of memory reconsolidation enables reversal of hyperalgesia. Nat Neurosci 17, 1043–1045 (2014). https://doi.org/10.1038/nn.3758

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