A cyclic peptide targeted against PSD-95 blocks central sensitization and attenuates thermal hyperalgesia.
Post-synaptic density protein PSD-95 is emerging as a valid target for modulating nociception in animal studies. Based on the key role of PSD-95 in neuronal plasticity and the maintenance of pain behavior, we predicted that CN2097, a peptide-based macrocycle of nine residues that binds to the PSD-95 Discs large, Zona occludens 1 (PDZ) domains of PSD-95, would interfere with physiologic phenomena in the spinal cord related to central sensitization. Furthermore, we tested whether spinal intrathecal injection of CN2097 attenuates thermal hyperalgesia in a rat model of sciatic neuropathy. Results demonstrate that spinal CN2097 reverses hyperexcitability of wide dynamic range (WDR) neurons in the dorsal horn of neuropathic rats and decreases their evoked responses to peripheral stimuli (brush, low caliber von Frey and pressure), whereas CN5125 ("negative control") has no effect. CN2097 also blocks C-fiber long-term potentiation (LTP) in the dorsal horn, which is linked to neuronal plasticity and central sensitization. At a molecular level, CN2097 attenuates the increase in phosphorylated p38 MAPK, a key intracellular signaling pathway in neuropathic pain. Moreover, spinal injection of CN2097 blocks thermal hyperalgesia in neuropathic rats. We conclude that CN2097 is a small molecule peptide with putative anti-nociceptive effects that modulates physiologic phenomena related to central sensitization under conditions of chronic pain.
LeBlanc
B W
BW
Department of Surgery, Rhode Island Hospital, Brown Alpert Medical School and Department of Neuroscience, Brown University, Providence, RI 02903, USA.
Iwata
M
M
Mallon
A P
AP
Rupasinghe
C N
CN
Goebel
D J
DJ
Marshall
J
J
Spaller
M R
MR
Saab
C Y
CY
D000200:Action Potentials / Q000187:drug effects; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D000076122:Disks Large Homolog 4 Protein; D006358:Hot Temperature; D006801:Humans; D006930:Hyperalgesia / Q000503:physiopathology / Q000517:prevention & control*; D007278:Injections, Spinal; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008024:Ligands; D017774:Long-Term Potentiation / Q000187:drug effects; D008161:Lumbosacral Region; D008565:Membrane Proteins / Q000378:metabolism*; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects / Q000502:physiology; D054731:PDZ Domains; D010146:Pain / Q000503:physiopathology / Q000517:prevention & control; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010523:Peripheral Nervous System Diseases / Q000503:physiopathology / Q000517:prevention & control; D010766:Phosphorylation; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000503:physiopathology; D013116:Spinal Cord / Q000187:drug effects* / Q000503:physiopathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000700:Analgesics; C550069:CN2097; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008565:Membrane Proteins; D010456:Peptides, Cyclic; D048051:p38 Mitogen-Activated Protein Kinases