Araldi D, Bogen O, Green PG, Levine JD. Role of Nociceptor Toll-like Receptor 4 (TLR4) in Opioid-Induced Hyperalgesia and Hyperalgesic Priming. (2019) J Neurosci 39(33):6414-6424. doi: 10.1523/JNEUROSCI.0966-19.2019
IT-10: IB4-SAP; IT-11: SSP-SAP
Objective: To evaluate the hypothesis that hyperalgesia and priming induced by opioids are mediated by similar nociceptor mechanisms.
Summary: Treatment with isolectin B4 (IB4)-saporin or SSP-SAP (which deplete IB4+ and peptidergic nociceptors, respectively), or their combination, prevented systemic LDM-induced hyperalgesia, but not priming. HDM-induced priming, but not analgesia, was markedly attenuated in both saporin-treated groups.
Dose: IB4-SAP was diluted in saline and a dose of 3.2 μg in a volume of 20 μl administered intrathecally. SSP-SAP was diluted in saline and a dose of 100 ng in a volume of 20 μl was administered intrathecally.
Pinto LG, Souza GR, Kusuda R, Lopes AH, Sant’Anna MB, Cunha FQ, Ferreira SH, Cunha TM. Non-Peptidergic Nociceptive Neurons Are Essential for Mechanical Inflammatory Hypersensitivity in Mice. (2019) Mol Neurobiol 56(8):5715-5728. doi: 10.1007/s12035-019-1494-5
Objective: To determine the role of non-peptidergic nociceptors in mediating mechanical inflammatory hypersensitivity in mice.
Summary: rIB4-SAP oblates non-peptidergic neurons as displayed by the decrease of purinoceptor 3. The depletion of these neurons inhibited the mechanical inflammatory sensitivity induced by GDMF and carrageenan, but not by other expected factors such as nerve growth factor implying the role of this subset of neurons to be one of mediation as opposed to direct nociception.
Dose: IB4-SAP (0.16–3.2 μg/5 μl, i.t.), unconjugated Saporin (as control, 1.8 μg/5 μl, i.t.), or saline (vehicle, 5 μl/i.t.) were injected into the subarachnoid space on the midline between the L5 and L6 vertebrae.
Araldi D, Khomula EV, Ferrari LF, Levine JD. Fentanyl Induces Rapid Onset Hyperalgesic Priming: Type I at Peripheral and Type II at Central Nociceptor Terminals. (2018) J Neurosci 38(9):2226-2245. doi: 10.1523/JNEUROSCI.3476-17.2018
Objective: To evaluate priming, at both nociceptor terminals, the effect of local administration of agents that reverse type I (protein translation) or type II [combination of Src and mitogen-activated protein kinase (MAPK)] priming.
Summary: Fentanyl, acting at the -opioid receptor (MOR), induces hyperalgesia and hyperalgesic priming at both the central and peripheral terminal of nociceptors and this is mediated by endoplasmic reticulum Ca2 signaling. Priming in the central terminal is type II, whereas that in the peripheral terminal is type I. Our findings may provide useful information for the design of drugs with improved therapeutic profiles, selectively disrupting individual MOR signaling pathways, to maintain an adequate long-lasting control of pain.
Dose: IB4-SAP was diluted in saline and a dose of 3.2 μg in a volume of 20 μl and administered intrathecally 14 d before experiments.
Ferrari LF, Khomula EV, Araldi D, Levine JD. CD44 Signaling Mediates High Molecular Weight Hyaluronan-Induced Antihyperalgesia. (2018) J Neurosci 38(2):308-321. doi: 10.1523/JNEUROSCI.2695-17.2017
Objective: To study the role of the cognate hyaluronan receptor, CD44, signaling in anti-hyperalgesia induced by high molecular weight hyaluronan (HMWH).
Summary: These results demonstrate the central role of CD44 signaling in HMWH-induced anti-hyperalgesia, and establish it as a therapeutic target against inflammatory and neuropathic pain.
Dose: Both IB4-SAP and SSP-SAP were diluted in saline to doses previously shown to deplete nonpeptidergic (3.2 mcg/rat for IB4-SAP) and peptidergic (100 ng/rat for SSP-SAP) fibers. The toxins were administered intrathecally, in a volume of 20 mcl, 14 d before intradermal injection of LMWH on the dorsum of the hindpaw. Treatment with either conjugate, or a combination of the two, did not significantly affect mechanical nociceptive threshold.
Israel MR, Morgan M, Tay B, Deuis JR. Toxins as tools: Fingerprinting neuronal pharmacology. (2018) Neurosci Lett 679:4-14. doi: 10.1016/j.neulet.2018.02.001
IT-10: IB4-SAP, IT-28: NPY-SAP
Summary: This review article provides an overview of the experimental techniques used to assess the effects that toxins have on neuronal function, as well as discussion on toxins that have been used as tools, with a focus on toxins that target voltage-gated and ligand-gated ion channels.
Watanabe S, Sakurai T, Nakamura S, Miyoshi K, & Sato M. The Combinational Use of CRISPR/Cas9 and Targeted Toxin Technology Enables Efficient Isolation of Bi-Allelic Knockout Non-Human Mammalian Clones. (2018). Int J Mol Sci, 19 (4)
Objective: Most genome editing systems employ transient treatment with selective drugs such as puromycin to obtain the desired genome-edited cells, which often allows some untransfected cells to survive and decreases the efficiency of generating genome-edited cells. The authors developed a novel targeted toxin-based drug-free selection system for the enrichment of genome-edited cells.
Summary: Results indicate that a combination of the CRISPR/Cas9 system and targeted toxin technology using IB4-SAP allows efficient enrichment of genome-edited clones, particularly bi-allelic KO clones.
Dose: Cells were trypsinized 3 days after transfection and approximately 80% were incubated for 30 min at 37°C in a solution (25 mcL) containing 0.5–1.0 mcg IB4-SAP.
Havelin J, Imbert I, Sukhtankar D, Remeniuk B, Pelletier I, Gentry J, Okun A, Tiutan T, Porreca F, & King TE. Mediation of Movement-Induced Breakthrough Cancer Pain by Ib4-Binding Nociceptors in Rats. (2017). J Neurosci, 37 (20):5111-5122. PMID: 28438966
Objective: To define a novel preclinical measure of movement-induced breakthrough pain (BTP) that is observed in the presence of morphine controlling ongoing pain.
Summary: Novel compounds targeting IB4-binding nociceptors may improve pain management for cancer pain patients and other patient populations suffering from BTP that is inadequately treated by currently available medications.
Dose: To determine the effect of eliminating input from IB4-binding fibers, separate groups of rats received spinal administration of IB4-SAP or the control, Blank-SAP (3.2 mcg/20 mcl saline) followed by a 10 mcl flush of saline. Movement of an air bubble placed between drug solution and saline was used to monitor progress of the injection.
Araldi D, Ferrari LF, Levine JD. (2016) Gi-Protein Coupled 5-HT1B/D Receptor Agonist Sumatriptan Induces Type I Hyperalgesic Priming. Pain 157(8):1773-82.PMID: 27075428 (Targeting Trends 16q3)
La JH, Feng B, Kaji K, Schwartz ES, Gebhart GF. (2016) Roles of isolectin B4-binding afferents in colorectal mechanical nociception. Pain 157(2):348-354. PMID: 26447707 (Targeting Trends 16q1)
Oyamaguchi A, Abe T, Sugiyo S, Niwa H, Takemura M. (2016) Selective elimination of isolectin B4-binding trigeminal neurons enhanced formalin-induced nocifensive behavior in the upper lip of rats and c-Fos expression in the trigeminal subnucleus caudalis. Neurosci Res 103:40-47. PMID: 26216055 (Targeting Trends 15q4)
Sakurai T, Kamiyoshi A, Kawate H, Mori C, Watanabe S, Tanaka M, Uetake R, Sato M, Shindo T. (2016) A Non-Inheritable Maternal Cas9-Based Multiple-Gene Editing System in Mice. Sci Rep 6:20011. PMID: 26817415 (Targeting Trends 17q1)
Araldi D, Ferrari LF, Levine JD. (2015) Repeated Mu-Opioid Exposure Induces a Novel Form of the Hyperalgesic Priming Model for Transition to Chronic Pain. J Neurosci 35(36):12502-12517. PMID: 26354917 (Targeting Trends 16q1)
Kras JV, Weisshaar CL, Pall PS, Winkelstein BA. (2015) Pain from intra-articular NGF or joint injury in the rat requires contributions from peptidergic joint afferents. Neurosci Lett 604:193-198. PMID: 26240991 (Targeting Trends 15q4)
Ono K, Ye Y, Viet CT, Dang D, Schmidt BL. (2015) TRPV1 expression level in isolectin B4-positive neurons contributes to mouse strain difference in cutaneous thermal nociceptive sensitivity. J Neurophysiol 113(9):3345-3355. (Targeting Trends 15q2)
Saeed AW, Pawlowski SA, Ribeiro-da-Silva A. (2015) Limited changes in spinal lamina I dorsal horn neurons following the cytotoxic ablation of non-peptidergic C-fibers. Mol Pain 11(1):54. PMID: 26353788 (Targeting Trends 15q4)
Sato M, Inada E, Saitoh I, Matsumoto Y, Ohtsuka M, Miura H, Nakamura S, Sakurai T, Watanabe S. (2015) A combination of targeted toxin technology and the piggyBac-mediated gene transfer system enables efficient isolation of stable transfectants in nonhuman mammalian cells. Biotechnol J 10(1):143-153. (Targeting Trends 15q1)
Sato M, Watanabe S. (2015) Drug-free selection of stable transfectants using targeted toxin technology and a vector expressing cell-surface carbohydrate-digesting enzyme. Targeting Trends 16(2).
Alvarez P, Green PG, Levine JD. (2014) Role for monocyte chemoattractant protein-1 in the induction of chronic muscle pain in the rat. Pain 155(6):1161-1167. (Targeting Trends 14q3)
Devesa I, Ferrandiz-Huertas C, Mathivanan S, Wolf C, Lujan R, Changeux JP, Ferrer-Montiel A. (2014) alphaCGRP is essential for algesic exocytotic mobilization of TRPV1 channels in peptidergic nociceptors. Proc Natl Acad Sci U S A 111(51):18345-18350. (Targeting Trends 15q2)
Sato M, Miyoshi K, Nagao Y, Nishi Y, Ohtsuka M, Nakamura S, Sakurai T, Watanabe S. (2014) The combinational use of CRISPR/Cas9-based gene editing and targeted toxin technology enables efficient biallelic knockout of the alpha-1,3-galactosyltransferase gene in porcine embryonic fibroblasts. Xenotransplantation 21(3):291-300. (Targeting Trends 14q3)
Ye Y, Bae S, Viet CT, Troob S, Bernabe D, Schmidt BL. (2014) IB4(+) and TRPV1(+) sensory neurons mediate pain but not proliferation in a mouse model of squamous cell carcinoma. Behav Brain Funct 10(1):5. (Targeting Trends 14q2)
Sato M, Akasaka E, Saitoh I, Ohtsuka M, Nakamura S, Sakurai T, Watanabe S. (2013) Targeted toxin-based selectable drug-free enrichment of Mammalian cells with high transgene expression. Biology (Basel) 2(1):341-355. (Targeting Trends 15q1)
Alvarez P, Chen X, Bogen O, Green PG, Levine JD. (2012) IB4(+) nociceptors mediate persistent muscle pain induced by GDNF. J Neurophysiol 108(9):2545-2553. (Targeting Trends 13q1)
Alvarez P, Gear RW, Green PG, Levine JD. (2012) IB4-saporin attenuates acute and eliminates chronic muscle pain in the rat. Exp Neurol 233(2):859-865. (Targeting Trends 12q2)
Taylor AM, Osikowicz M, Ribeiro-da-Silva A. (2012) Consequences of the ablation of nonpeptidergic afferents in an animal model of trigeminal neuropathic pain. Pain 153(6):1311-1319. (Targeting Trends 12q3)
Tolner EA, Sheikh A, Yukin AY, Kaila K, Kanold PO. (2012) Subplate neurons promote spindle bursts and thalamocortical patterning in the neonatal rat somatosensory cortex. J Neurosci 32(2):692-702. (Targeting Trends 12q2)
Ye Y, Dang D, Viet CT, Dolan JC, Schmidt BL. (2012) Analgesia Targeting IB4-Positive Neurons in Cancer-Induced Mechanical Hypersensitivity. J Pain 13(6):524-531. (Targeting Trends 12q3)
Akasaka E, Watanabe S, Himaki T, Ohtsuka M, Yoshida M, Miyoshi K, Sato M (2010) Enrichment of xenograft-competent genetically modified pig cells using a targeted toxin, isolectin BS-I-B4 conjugate. Xenotransplantation 17:81-89. (Targeting Trends 10q2)
Joseph EK, Levine JD (2010) Mu and delta opioid receptors on nociceptors attenuate mechanical hyperalgesia in rat. Neuroscience 171(1):344-350. (Targeting Trends 10q4)
Joseph EK, Levine JD (2010) Hyperalgesic priming is restricted to isolectin B4-positive nociceptors. Neuroscience 169(1):431-435. (Targeting Trends 10q3)
Bogen O, Dina OA, Gear RW, Levine JD (2009) Dependence of monocyte chemoattractant protein 1 induced hyperalgesia on the isolectin B4-binding protein versican. Neuroscience 159:780-786. (Targeting Trends 09q2)
Bogen O, Joseph EK, Chen X, Levine JD (2008) GDNF hyperalgesia is mediated by PLCgamma, MAPK/ERK, PI3K, CDK5 and Src family kinase signaling and dependent on the IB4-binding protein versican. Eur J Neurosci 28:12-19. (Targeting Trends 08q4)
Joseph EK, Chen X, Bogen O, Levine JD (2008) Oxaliplatin Acts on IB4-Positive Nociceptors to Induce an Oxidative Stress-Dependent Acute Painful Peripheral Neuropathy. J Pain 9:463-472. ((Targeting Trends 08q2)(Targeting Trends 08q2))
Zinck ND, Downie JW (2008) IB4 afferent sprouting contributes to bladder dysfunction in spinal rats. Exp Neurol 213:293-302. (Targeting Trends 08q4)
Lappi DA (2005) Targeted Toxins from Here to There. Targeting Trends 6(3):1, 6.
Pearson M. (2005) IB4-SAP Prevents Axotomy-Induced Sprouting of Aß Fibers. Targeting Trends 6(1).
Nishiguchi J, Sasaki K, Seki S, Chancellor MB, Erickson KA, de Groat WC, Kumon H, Yoshimura N (2004) Effects of isolectin B4-conjugated saporin, a targeting cytotoxin, on bladder overactivity induced by bladder irritation. Eur J Neurosci 20(2):474-482. (Targeting Trends 04q3)
Sedel F, Béchade C, Vyas S, Triller A (2004) Macrophage-derived tumor necrosis factor alpha, an early developmental signal for motoneuron death. J Neurosci 24(9):2236-2246.
Tarpley JW, Kohler MG, Martin WJ (2004) The behavioral and neuroanatomical effects of IB(4)-saporin treatment in rat models of nociceptive and neuropathic pain. Brain Res 1029(1):65-76. (Targeting Trends 05q1)(Targeting Trends 05q1)
Yoshimura N. (2004) Effects of IB4-SAP on Bladder Overactivity. Targeting Trends 5(4).
See also: Society for Neuroscience 2004 Abstracts
Lappi D. (2003) Biotinylated targeting. A viable option? Targeting Trends 4(2).
Nakatsuka T, Tsuzuki K, Ling JX, Sonobe H, Gu JG (2003) Distinct roles of P2X receptors in modulating glutamate release at different primary sensory synapses in rat spinal cord. J Neurophysiol 89(6):3243-3252. (Targeting Trends 03q3)
Vulchanova L, Olson TH, Stone LS, Riedl MS, Elde R, Honda CN (2001) Cytotoxic targeting of isolectin IB4-binding sensory neurons. Neurosci 108(1):143-155. (Targeting Trends 02q2)
See also: Society for Neuroscience 2001 Abstracts
Basbaum AI (1999) Distinct neurochemical features of acute and persistent pain. Proc Natl Acad Sci USA 96:7739-7743.
Snider WD, McMahon SB (1998) Tackling pain at the source: New ideas about nociceptors. Neuron 20:629-632.