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Current and future issues in the development of spinal agents for the management of pain.
Yaksh T, Fisher C, Hockman T, Wiese A (2017) Current and future issues in the development of spinal agents for the management of pain. Curr Neuropharmacol 15:232-259.. doi: 10.2174/1570159×14666160307145542
Summary: Although conscious pain experience is driven by signals mediated supraspinally, the more high intensity pain generated by strong stimuli, tissue injury, and nerve injury is encoded at the spinal dorsal horn level. The control of pain signals at the spinal dorsal horn level is a tempting target for targeted pain therapy. This review discusses the potential targets for pain therapeutics in the spinal dorsal horn, and some of the spinal agents used to modulate pain transmission through that location. The use of SSP-SAP (Cat. #IT-11) is mentioned as a neurokinin-1 targeted molecule that can block some pain transmission.
Related Products: SSP-SAP (Cat. #IT-11)
Gi-protein-coupled 5-HT1B/D receptor agonist sumatriptan induces type I hyperalgesic priming.
Araldi D, Ferrari L, Levine J (2016) Gi-protein-coupled 5-HT1B/D receptor agonist sumatriptan induces type I hyperalgesic priming. Pain 157:1773-1782. doi: 10.1097/j.pain.0000000000000581
Summary: The present study explored the possibility that, like MOR and A1-adenosine receptor agonists, triptans would also induce type II hyperalgesic priming. In addition, they explored the 5-HT receptor subtypes at which triptans act (5-HT1B, 5-HT1D and 5-HT7) to induce priming. They report that while sumatriptan, a prototypical 5-HT1B/D receptor agonist induces hyperalgesic priming, this priming meets the criteria for type I rather than type II priming. Isolectin B4 (IB4)-saporin (Cat. #IT-10), was diluted in saline, and a dose of 3.2 μg, in a volume of 20 μL was administered intrathecally to rats. The neurotoxin [Sar9,Met(O2) 11]-substance P-saporin (SSP-Saporin, Cat. #IT-11) was diluted in saline, and a dose of 100 ng, in a volume of 20 μL was administered intrathecally. In a model of pain chronification, sumatriptan induces both mechanical hyperalgesia at the site of injection and type I hyperalgesic priming, in nociceptors innervating the cutaneous injection site.
Related Products: IB4-SAP (Cat. #IT-10), SSP-SAP (Cat. #IT-11)
Functional characterization of a mouse model for central post-stroke pain.
Gritsch S, Bali K, Kuner R, Vardeh D (2016) Functional characterization of a mouse model for central post-stroke pain. Mol Pain 12:1744806916629049. doi: 10.1177/1744806916629049
Summary: While clinical evidence has pointed toward central pain pathway dysfunction in central post-stroke pain (CPSP), the underlying mechanisms have not been defined. In this work the authors created a mouse model of CPSP through lesions of the thalamic ventral posterolateral nucleus. In order to examine the role of neurokinin-1 receptor-expressing (NK1R) neurons in lamina I/III of the spinal cord in the development and maintenance of CPSP the authors administered 1 μmol intrathecal injections of SSP-SAP (Cat. #IT-11). Saporin (Cat. #PR-01) was used as a control. While the NK1R+ neurons in the spinal cord were not involved in establishing CPSP, the data indicate that sensory changes in the mice are comparable to those observed in human patients with CPSP.
Related Products: SSP-SAP (Cat. #IT-11), Saporin (Cat. #PR-01)
Pain from intra-articular NGF or joint injury in the rat requires contributions from peptidergic joint afferents.
Kras J, Weisshaar C, Pall P, Winkelstein B (2015) Pain from intra-articular NGF or joint injury in the rat requires contributions from peptidergic joint afferents. Neurosci Lett 604:193-198. doi: 10.1016/j.neulet.2015.07.043
Summary: Both peptidergic and non-peptidergic neurons innervate the facet joint, which is the source of pain in a majority of neck trauma. In this work the authors examined these subpopulations of neurons to determine the contribution of each in facet joint pain. 100 ng of SSP-SAP (Cat. #IT-11) was injected into bilateral C6/C7 facet joints of rats. Alternatively, rats received 5 μg of rIB4-SAP (Cat. #IT-10) via the same method. Saporin (Cat. #PR-01) was used as control. SSP-SAP, but not rIB4-SAP was able to prevent NGF-induced mechanical and thermal hypersensitivity. SSP-SAP administration also prevented behavioral hypersensitivity and NGF upregulation in the dorsal root ganglion after facet joint distraction. The data indicate that interference with peptidergic signaling within the facet joint may be a treatment for pain originating in that location.
Related Products: SSP-SAP (Cat. #IT-11), IB4-SAP (Cat. #IT-10), Saporin (Cat. #PR-01)
A central role for spinal dorsal horn neurons that express neurokinin-1 receptors in chronic itch.
Akiyama T, Nguyen T, Curtis E, Nishida K, Devireddy J, Delahanty J, Carstens M, Carstens E (2015) A central role for spinal dorsal horn neurons that express neurokinin-1 receptors in chronic itch. Pain 156:1240-1246. doi: 10.1097/j.pain.0000000000000172
Summary: Chronic itch is caused by increased sensitivity of itch-signaling pathways. It can be generated by normally itchy stimuli (hyperknesis) and by normally non-itchy light touch (alloknesis). The authors used an ovalbumin-induced atopic dermatitis model to study chronic itch in mice. The mice received 400-ng intrathecal injections of Bombesin-SAP (Cat. #IT-40), SSP-SAP (Cat. #IT-11), or the control Blank-SAP (Cat. #IT-21). While Bombesin-SAP significantly attenuated hyperknesis, it had no effect on spontaneous scratching or alloknesis. SSP-SAP reduced all behavioral signs of chronic itch.
Related Products: Bombesin-SAP (Cat. #IT-40), SSP-SAP (Cat. #IT-11), Blank-SAP (Cat. #IT-21)
NK1-receptor-expressing paraventricular nucleus neurones modulate daily variation in heart rate and stress-induced changes in heart rate variability.
Feetham C, Barrett-Jolley R (2014) NK1-receptor-expressing paraventricular nucleus neurones modulate daily variation in heart rate and stress-induced changes in heart rate variability. Physiol Rep 2:e12207. doi: 10.14814/phy2.12207
Summary: Neurons in the paraventricular nucleus (PVN) project to the medulla and spinal cord, regulating heart rate and blood pressure. Although the activity of these neurons becomes elevated during heart failure, their role in overall cardiovascular control is unclear. The authors lesioned the PVN of rats with 2 ng injections of SSP-SAP (Cat. #IT-11). Heart rate variability during the experiment was measured using a high/low frequency ratio in response to psychological stress. The variability response of lesioned rats was lower than that of controls, and a shift in daily heart rate variation was seen as well. The authors conclude that neurokinin-1 expressing neurons in the PVN couple the cardiovascular system to the daily heart rate as well as the sympathetic response to psychological stress.
Related Products: SSP-SAP (Cat. #IT-11)
Expression of different neurokinin-1 receptor (NK1R) isoforms in glioblastoma multiforme: potential implications for targeted therapy.
Cordier D, Gerber A, Kluba C, Bauman A, Hutter G, Mindt TL, Mariani L (2014) Expression of different neurokinin-1 receptor (NK1R) isoforms in glioblastoma multiforme: potential implications for targeted therapy. Cancer Biother Radiopharm 29(5):221-226. doi: 10.1089/cbr.2013.1588
Summary: The neurokinin-1 receptor (NK1r) has been found to be consistently over-expressed in gliomas, making it a potential target for therapeutic strategies. However, treatments with therapies utilizing substance P (SP), the ligand for the NK1r, have at best yielded uneven results. In this work the authors investigated factors that may predict the response to therapies directed at NK1r gliomas. SSP-SAP (Cat. #IT-11) was used at a concentration of 1 nM in cytotoxicity assays on several different glioma cell lines. Using this and other data it was shown that only the cell line with the most full-length NK1r RNA transcripts displayed high levels of binding, internalization, and cell killing necessary for NK1r to be a therapeutic target using SP.
Related Products: SSP-SAP (Cat. #IT-11)
Ablating spinal NK1-bearing neurons eliminates the development of pain and reduces spinal neuronal hyperexcitability and inflammation from mechanical joint injury in the rat.
Weisshaar CL, Winkelstein BA (2014) Ablating spinal NK1-bearing neurons eliminates the development of pain and reduces spinal neuronal hyperexcitability and inflammation from mechanical joint injury in the rat. J Pain 15(4):378-386. doi: 10.1016/j.jpain.2013.12.003
Summary: A high percentage of chronic neck pain involves the facet joint. Although the facet joint is innvervated by peptide-responsive nociceptive afferents, the role of these cells in the development and modulation of nociceptive signaling remains unclear. Using a previously developed rat model of facet joint injury, the authors examined the role of neurokinin-1 receptor-expressing spinal cells in this pathway. Rats received 100 ng SSP-SAP (Cat. #IT-11) via lumbar puncture. Blank-SAP (Cat. #IT-21) was used as a control. The results demonstrate that spinal NK1r-expressing cells are essential for nociception and inflammation due to a mechanical joint injury.
Related Products: SSP-SAP (Cat. #IT-11), Blank-SAP (Cat. #IT-21)
Phox2b-expressing retrotrapezoid neurons and the integration of central and peripheral chemosensory control of breathing in conscious rats.
Takakura AC, Barna BF, Cruz JC, Colombari E, Moreira TS (2014) Phox2b-expressing retrotrapezoid neurons and the integration of central and peripheral chemosensory control of breathing in conscious rats. Exp Physiol 99(3):571-585. doi: 10.1113/expphysiol.2013.076752
Summary: Previous work has shown that lesions to the retrotrapezoid nucleus (RTN) have at least a modest effect on breathing, but it is unclear whether those lesions affected the entire nucleus or were incomplete. The authors used bilateral lesions of the RTN with 0.3 to 1.2 ng total of SSP-SAP (Cat. #IT-11) to eliminate neurokinin-1 receptor-expressing neurons; these are also Phox2b+TH- neurons. The results indicate that loss of Phox2b(+)TH(-) neurons may cause deficits seen after RTN lesion, and help define the ways in which these cells are involved in controlling central and peripheral chemoreflexes.
Related Products: SSP-SAP (Cat. #IT-11)
Loss of neurons in rostral ventromedial medulla that express neurokinin-1 receptors decreases the development of hyperalgesia.
Khasabov SG, Simone DA (2013) Loss of neurons in rostral ventromedial medulla that express neurokinin-1 receptors decreases the development of hyperalgesia. Neuroscience 250C:151-165. doi: 10.1016/j.neuroscience.2013.06.057
Summary: Previous data has indicated that neurokinin-1 receptors are located on ON cells in the rostral ventromedial medulla (RVM). ON cells are considered pronociceptive because noxious stimulation is stimulatory. In this work the authors eliminated ON cells using 0.3-μl injections of 1 μM SSP-SAP (Cat. #IT-11) into the left and right side of the RVM. Blank-SAP (Cat. #IT-21) was used as a control. SSP-SAP treatment did not change mechanical or heat withdrawal responses, or change morphine-induced analgesia. A significant reduction in the duration of nocifensive behaviors induced by various hyperalgesic stimulators indicated that these neurons are involved in pain facilitation rather than modulation.
Related Products: SSP-SAP (Cat. #IT-11), Blank-SAP (Cat. #IT-21)