Targeting Topics 10q4

Mu and delta opioid receptors on nociceptors attenuate mechanical hyperalgesia in rat

Joseph EK, Levine JD

Neuroscience 171(1):344-350, 2010.

In this work the authors analyzed nociceptor populations mediating mechanical hyperalgesia in the rat. Rats received 3.2 µg of IB4-SAP (Cat. #IT-10) into the subarachnoid space between the L4 and L5 vertebrae. Hyperalgesia due to the administration of NGF was inhibited by DAMGO and SNC even in lesioned animals. These data indicate that most nociceptor populations are involved in mechanical hyperalgesia, and that the mu opioid and delta opioid receptors are co-expressed on some trkA-positive nociceptors.

Induction of CD4(+)CD25(+) T regulatory cells with CD103 depletion

Zikri NN, Schumer E, Wang JJ, Gaughan A, Hadley GA, Moffatt-Bruce SD

J Surg Res 163(1):162-168, 2010.

CD8+ T cells expressing CD103 have been shown to play a key role in the rejection of renal allografts. Use of M290-SAP (a custom saporin conjugation) allows allograft tolerance even in a completely mismatched islet cell transplant model. Use of 1 mg M290-SAP/kg body weight in mice allowed the authors to characterize the kinetics of M290-SAP and its induction of CD4 CD25 regulatory T cells.

Saporin toxin-conjugated monoclonal antibody targeting prostate-specific membrane antigen has potent anticancer activity

Kuroda K, Liu H, Kim S, Guo M, Navarro V, Bander NH

Prostate 70(12):1286-1294, 2010.

Current treatments for prostate cancer are only moderately effective. In this work the authors examined the cytotoxic efficacy of a prostate-specific membrane antigen (PMSA) antibody conjugated to saporin on PMSA-positive cell lines. hJ591, a humanized PMSA antibody, was biotinylated and combined with streptavidin-ZAP (Cat. #IT-27). The hJ591-streptavidin-ZAP complex was specifically cytotoxic to PMSA-positive cell lines, and had anti-cancer activity in a xenograft model. This work demonstrates the anti-cancer potential of targeting PMSA.

Septohippocampal pathways contribute to system consolidation of a spatial memory: Sequential implication of gabaergic and cholinergic neurons

Lecourtier L, de Vasconcelos AP, Leroux E, Cosquer B, Geiger K, Lithfous S, Cassel JC

Hippocampus Epub, 2010.

Few studies have examined the role of GABAergic septohippocampal projections in memory consolidation. The authors administered 192-IgG-SAP (400 ng; Cat. #IT-01) and/or orexin-SAP (70 ng; Cat. #IT-20 discontinued) to the medial septum/vertical limb of the diagonal band of Broca of rats. Spatial memory tests were then administered over several weeks. The data indicate that both GABAergic and cholinergic septohippocampal systems contribute to memory stabilization, possibly in a sequential manner.

A new oxytocin-saporin cytotoxin for lesioning oxytocin-receptive neurons in the rat hindbrain

Baskin DG, Kim F, Gelling RW, Russell BJ, Schwartz MW, Morton GJ, Simhan HN, Moralejo DH, Blevins JE

Endocrinology 151(9):4207-4213, 2010.

Evidence suggests that release of oxytocin in the nucleus tractus solitarius (NTS) of the hindbrain can inhibit food intake by augmenting the cholecystokinin satiety response. The authors used oxytocin-SAP (Cat. #IT-46) to eliminate oxytocin receptive cells in the NTS. Blank-SAP (Cat. #IT-21) was used as a control. 0.5 µl-injections of oxytocin-SAP into the NTS caused reduced satiation effect of CCK-8 and blocked the stimulation of food intake by an oxytocin receptor antagonist.

Contribution of limbic norepinephrine to cannabinoid-induced aversion

Carvalho AF, Reyes AR, Sterling RC, Unterwald E, Van Bockstaele EJ

Psychopharmacology (Berl) 211(4):479-491, 2010.

The authors used bilateral injections of anti-DBH-SAP (Cat. #IT-03) into the nucleus accumbens and the bed nucleus of the stria terminalis to investigate the role of neuroepinephrine in cannabinoid-induced aversion and anxiety. Lesioned animals received bilateral 52.5-ng injections of anti-DBH-SAP into the nucleus accumbens or 63 ng into the bed nucleus of the stria terminalis. Saporin (Cat. #PR-01) was used as a control. Lesioned animals displayed reversed aversive behavior, but no change in anxiety-like behavior.

Noradrenergic Nuclei that Receive Sensory Input During Mating and Project to the Ventromedial Hypothalamus Play a Role in Mating-Induced Pseudopregnancy in the Female Rat

Northrop LE, Polston EK, Erskine MS

J Neuroendocrinol 22(10):1061-1071, 2010.

Maintenance of pregnancy or pseudo-pregnancy in rats is maintained by bicircadian prolactin surges induced by vaginal-cervical stimulation. In order to test the hypothesis that medullary noradrenergic cell groups are involved in this process the authors infused rats with either 2 ng or 60 ng anti-DBH-SAP (Cat. #IT-03) into the ventrolateral division of the ventromedial hypothalamus and the posterodorsal medial amygdala. Mouse IgG-SAP (Cat. #IT-18) was used as a control. The data confirm that noradrenergic neurons are involved in the maintenance of pregnancy or pseudopregnancy.

Decrease in membrane phospholipid unsaturation induces unfolded protein response

Ariyama H, Kono N, Matsuda S, Inoue T, Arai H

J Biol Chem 285(29):22027-22035, 2010.

Properties of the cell membrane can be influenced by the degree of fatty acid unsaturation in membrane phospholipids. Alteration of this unsaturation has been implicated in many disease states. Using an SCD1 antibody (Cat. #AB-259) to visualize SCD1 levels by western blot, the authors determined that there are several genetic factors that affect the level of saturated fatty acid in systems modulating insulin resistance, type 2 diabetes, and cardiovascular disease.

NK-1-receptor-mediated lesion of spinal post-synaptic dorsal column neurons might improve intractable visceral pain of cancer origin

Wang Y, Mu X, Liu Y, Zhang X, Wu A, Yue Y

Med Hypotheses 76(1):102-104, 2011.

There is evidence that spinal post-synaptic dorsal column neurons begin to express neurokinin-1 receptors after visceral stimulation. The authors discuss using this expression profile to target SSP-SAP (Cat. #IT-11) to these neurons and eliminate them. This use of ‘molecular neurosurgery’ may be a replacement for traditional neurosurgery for the treatment of cancer-related visceral pain.

Photochemical internalization (PCI): a technology for drug delivery

Berg K, Weyergang A, Prasmickaite L, Bonsted A, Hogset A, Strand MT, Wagner E, Selbo PK

Methods Mol Biol 635:133-145, 2010.

This review discusses photochemical internalization (PCI), which is a method used to overcome some of the intracellular barriers to introducing molecules into cancer cells. Some difficulties for such therapies include a low rate of release from endocytic vesicles and degradation of the therapeutic molecule by lysosomal enzymes. The use of streptavidin-ZAP (Cat. #IT-27) with a biotinylated EGF receptor antibody is discussed.

Distinct neural pathways mediate alpha7 nicotinic acetylcholine receptor-dependent activation of the forebrain

Thomsen MS, Hay-Schmidt A, Hansen HH, Mikkelsen JD

Cereb Cortex 20(9):2092-2102, 2010.

In this work the authors examine the systems controlling cognitive function in the medial prefrontal cortex (mPFC) and nucleus accumbens shell (ACCshell). Rats received 30-ng injections of 192-IgG-SAP (Cat. #IT-01) into the horizontal limb of the diagonal band of Broca, eliminating the cortically-projecting cholinergic neurons. Deficits in the basal forebrain and the mPFC are shown to be involved in attentional function, while deficits in the ACCshell are shown to be involved in the beneficial effects of antipsychotics on schizophrenia.

Effect of applying p75NTR saporin to a punctured intervertebral disc on calcitonin gene-related peptide expression in rat dorsal root ganglion neurons

Sugiura A, Ohtori S, Yamashita M, Yamauchi K, Inoue G, Suzuki M, Norimoto M, Orita S, Eguchi Y, Kuniyoshi K, Ochiai N, Kishida S, Takaso M, Aoki Y, Ishikawa T, Arai G, Miyagi M, Kamoda H, Nakamura J, Takahashi K

J Orthop Sci 15(3):407-413, 2010.

Lumbar intervertebral discs are suspected to be a source of low back pain, in part because of the innervation of these discs by neurons containing substance P and CGRP receptors. Rats received 2.5 µg of 192-IgG-SAP (Cat. #IT-01) into the L5/6 vertebral disc after the disc was punctured. While half of the dorsal root ganglion neurons innervating the disc were positive for CGRP post-puncture, animals receiving 192-IgG-SAP displayed reduced CGRP expression, indicating a role for the p75 receptor in discogenic pain.

Postnatal development and functional adaptations of the melanopsin photoreceptive system in the albino mouse retina

Gonzalez-Menendez I, Contreras F, Cernuda-Cernuda R, Provencio I, Garcia-Fernandez JM

Invest Ophthalmol Vis Sci 51(9):4840-4847, 2010.

Melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) adjust the circadian pacemaker of mammals by detecting light. The authors tracked the development of ipRGCs in postnatal mice under varying light conditions. Immunohistochemistry for these experiments was done using a melanopsin polyclonal antibody (Cat. #AB-N38). Alteration of the standard light/dark cycle clearly affected the development of ipRGCs.

Noradrenergic neurons of the area postrema mediate amylin’s hypophagic action

Potes CS, Turek VF, Cole RL, Vu C, Roland BL, Roth JD, Riediger T, Lutz TA

Am J Physiol Regul Integr Comp Physiol 299(2):R623-631, 2010.

The neuronal pathways used to process the physiological response to amylin were investigated using 50-ng injections of anti-DBH-SAP (Cat. #IT-03) into the area postrema (AP) or 25 ng into the lateral parabrachial nucleus. Mouse IgG-SAP (Cat. #IT-18) was used as a control. The response to amylin administration (reduction of food intake) was significantly reduced in lesioned animals, indicating that noradrenergic neurons in the AP control at least part of this pathway.

Substance P modulation of hypoglossal motoneuron excitability during development: changing balance between conductances

Adachi T, Huxtable AG, Fang X, Funk GD

J Neurophysiol 104(2):854-872, 2010.

This work examined how neuromuscular networks that are immature, but functional, at birth move through development while remaining operational. The authors focused on hypoglossal motoneurons involved in behaviors such as swallowing, suckling, and breathing. Immunohistochemistry was performed using an NK-1 receptor antibody (Cat. #AB-N04, discontinued). The data show that although NK-1 receptor density decreases as the animal matures, substance P (the NK-1 receptor ligand) remains an important part of these networks.

Orexin-B-saporin lesions in the lateral hypothalamus enhance photic masking of rapid eye movement sleep in the albino rat

Ocampo-Garces A, Ibanez F, Perdomo G, Torrealba F

J Sleep Res 20(1 Pt 1):3-11, 2011.

Photic masking occurs when photic input to the retina interferes with REM sleep. Rats that received 200 ng of orexin-SAP (Cat. #IT-20, discontinued) into the lateral hypothalamus experienced dramatically less REM sleep during normal light cycles. Placing them in a skeleton photoperiod (brief pulses of light, one in the morning and one in the evening), however, caused REM sleep during the rest phase to return to normal. These data suggest that photic masking may explain some effects of narcolepsy and cataplexy.