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Nocistatin, a peptide that blocks nociceptin action in pain transmission
E Okuda-Ashitaka1, T Minami, S Tachibana
1Department of Medical Chemistry, Kansai Medical University, Moriguchi, Japan.
Abstract:
Prolonged tissue damage or injury often leads to chronic pain states such that noxious stimuli evoke hyperalgesia and innocuous tactile stimuli evoke pain (allodynia). The neuropeptide nociceptin, also known as orphanin FQ, is an endogenous ligand for the orphan opioid-like receptor which induces both hyperalgesia and allodynia when administered by injection through the theca of the spinal cord into the subarachnoid space (that is, intrathecally). Here we show that the nociceptin precursor contains another biologically active peptide which we call nocistatin. Nocistatin blocks nociceptin-induced allodynia and hyperalgesia, and attenuates pain evoked by prostaglandin E2. It is the carboxy-terminal hexapeptide of nocistatin (Glu-Gln-Lys-Gln-Leu-Gln), which is conserved in bovine, human and murine species, that possesses allodynia-blocking activity. We have also isolated endogenous nocistatin from bovine brain. Furthermore, intrathecal pretreatment with anti-nocistatin antibody decreases the threshold for nociceptin-induced allodynia. Although nocistatin does not bind to the nociceptin receptor, it binds to the membrane of mouse brain and of spinal cord with high affinity. Our results show that nocistatin is a new biologically active peptide produced from the same precursor as nociceptin and indicate that these two peptides may play opposite roles in pain transmission.
Insights
A newly discovered peptide, nocistatin, derived from the nociceptin precursor, effectively blocks pain and hyperalgesia. This finding suggests nocistatin and nociceptin may have opposing roles in pain signaling pathways.
Area of Science:
- Neuroscience
- Pain Research
- Molecular Biology
Background:
- Chronic pain involves hyperalgesia and allodynia.
- Nociceptin (orphanin FQ) induces hyperalgesia and allodynia when administered intrathecally.
- The endogenous opioid-like receptor ligand nociceptin plays a role in pain transmission.
Purpose of the Study:
- To identify and characterize a novel peptide from the nociceptin precursor.
- To investigate the role of this new peptide in pain modulation.
- To explore the interaction between nociceptin and the newly identified peptide.
Main Methods:
- Administration of nociceptin and nocistatin intrathecally.
- Assessment of nocistatin's effect on nociceptin-induced hyperalgesia and allodynia.
- Testing nocistatin's efficacy against prostaglandin E2-evoked pain.
- Isolation of endogenous nocistatin from bovine brain.
- Utilizing anti-nocistatin antibodies to evaluate nociceptin-induced allodynia.
- Investigating nocistatin's binding affinity to neuronal membranes.
Main Results:
- A novel peptide, nocistatin, was identified from the nociceptin precursor.
- Nocistatin effectively blocked nociceptin-induced allodynia and hyperalgesia.
- The carboxy-terminal hexapeptide of nocistatin demonstrated allodynia-blocking activity.
- Endogenous nocistatin was isolated from bovine brain.
- Anti-nocistatin antibodies enhanced nociceptin-induced allodynia.
- Nocistatin exhibits high-affinity binding to mouse brain and spinal cord membranes, distinct from the nociceptin receptor.
Conclusions:
- Nocistatin is a new biologically active peptide derived from the nociceptin precursor.
- Nocistatin and nociceptin appear to exert opposing effects on pain transmission.
- Nocistatin represents a potential therapeutic target for managing chronic pain states.