Zeta Inhibitory Peptide as a Novel Therapy to Control Chronic Visceral Hypersensitivity in a Rat Model

Abstract

BackgroundThe pathogenesis of multiple chronic visceral pain syndromes, such as irritable bowel syndrome (IBS), is not well known, and as a result current therapies are ineffective. The objective of this study was to investigate the effect of spinal protein kinase M zeta (PKMζ) on visceral pain sensitivity in rats with IBS to better understand the pathogenesis and investigate the effect of zeta inhibitory peptide (ZIP) as a therapy for chronic visceral pain.MethodsVisceral hypersensitivity rats were produced by neonatal maternal separation (NMS). Visceral pain sensitivity was assessed by electromyographic (EMG) responses of abdominal muscles to colorectal distention (CRD). Spinal PKMζ and phosphorylated PKMζ (p-PKMζ) were detected by western blot. Varying doses of ZIP were intrathecally administered to investigate the role of spinal PKMζ in chronic visceral hypersensitivity. The open field test was used to determine if ZIP therapy causes spontaneous motor activity side effects.ResultsGraded CRD pressure significantly increased EMG responses in NMS rats compared to control rats (p < 0.05). p-PKMζ expression increased in the thoracolumbar and lumbosacral spinal cord in the IBS-like rats with notable concomitant chronic visceral pain compared to control rats (p < 0.05). EMG data revealed that intrathecal ZIP injection (1, 5, and 10 μg) dose-dependently attenuated visceral pain hypersensitivity in IBS-like rats.ConclusionsPhosphorylated PKMζ may be involved in the spinal central sensitization of chronic visceral hypersensitivity in IBS, and administration of ZIP could effectively treat chronic visceral pain with good outcomes in rat models.

Blockade of BDNF signalling attenuates chronic visceral hypersensitivity in an IBS‐like rat model

“…Brain‐derived neurotrophic factor increases PKMζ protein expression at the spinal synapses in a chronic allodynia pain state (Melemedjian et al, ). We previously found that PKMζ or pPKMζ expression increased in the hippocampus (Chen et al, ) or the spinal segments of IBS‐like model rats (Tang et al, ). Furthermore, we found that BDNF expression was enhanced in NMS rats; is it possible that BDNF could regulate PKMζ expression?…”

“…Male Sprague–Dawley rats were provided from the Department of the Experimental Animal Center of Fujian Medical University. NMS was established as described previously (Tang et al, ). Briefly, on postnatal 3–21 days neonates were separated from their mothers for 180 min every day.…”

“…Inhibiting PKMζ in the anterior cingulate cortex alleviated neuropathic pain (Ko et al, 2018;Li et al, 2010). Previously, we found that zeta inhibitory peptide (an inhibitor of PKMζ) could attenuate chronic visceral hypersensitivity in rats subjected to neonatal maternal separation (NMS; Tang et al, 2016); PKMζ is an atypical specific protein kinase C that is involved downstream of phospholipase Cγ1, in one of the three main intracellular signalling cascades activated by the TrkB (Huang & Reichardt, 2003;Reichardt, 2006). BDNF and PKMζ compensate for each other to maintain LTP (Sajikumar & Korte, 2011).…”

Predisposition of Neonatal Maternal Separation to Visceral Hypersensitivity via Downregulation of Small-Conductance Calcium-Activated Potassium Channel Subtype 2 (SK2) in Mice

“…Separation of pups from their dams was conducted daily for 6 h as of postnatal day 2 to15, with distinction from studies of MS models established by separating pups from their dams 3 h daily. As per their findings, separation for 3 h daily can develop somatic and visceral hyperalgesia as well [ 49 – 52 ]. Nevertheless, we have recognized that exposure to MS 3 h daily could not develop visceral hypersensitivity in adulthood, whereas separation for 6 h daily could successfully induce visceral hypersensitivity, which was contrary to the abovementioned results [ 51 , 52 ] and consistent with our previous reports [ 53 ].…”

Blockage of High-Affinity Choline Transporter Increases Visceral Hypersensitivity in Rats with Chronic Stress

“…AWR and threshold pressure of CRD which induced the first contraction of abdominal muscles were assessed in a blinded manner. As previous studies [ 18 , 23 ], rats were anaesthetized by isoflurane using an anesthetic equipment (AS-01-0007, Summit, USA). Connected with syringe and sphygmomanometer, a balloon was inserted into the colorectum after lubrication.…”