Targeting Topics 06q3

Toward better pain control.

Basbaum AI, Julius D.

Sci Am 294(6):60-67, 2006.

The authors discuss some of the advances in understanding and treating different types of pain, and specifically outline circuits, receptors, and ligands involved in pain pathways. Several treatments are described, one of which is the use of SP-SAP (Cat. #IT-07) to disrupt the chronic pain pathway in the spinal cord.

Hypotensive hypovolemia and hypoglycemia activate different hindbrain catecholamine neurons with projections to the hypothalamus.

Dinh TT, Flynn FW, Ritter S.

Am J Physiol Regul Integr Comp Physiol 291(4):R870-9, 2006.

Hypovolemia, a decrease in blood plasma volume, results in secretion of arginine vasopressin (AVP). This work investigates the role of hindbrain catecholamine neurons in hypovolemia-induced AVP secretion. Rats were treated with bilateral 42 ng injections of anti-DBH-SAP (Cat. #IT-03) into the paraventricular nucleus of the hypothalamus, and hypovolemia was induced by blood withdrawal. Treated animals displayed severely impaired AVP response, as well as lower food intake and corticosterone secretion in response to insulin.

Aversive stimulus attenuates impairment of acquisition in a delayed match to position T-maze task caused by a selective lesion of septo-hippocampal cholinergic projections.

Fitz NF, Gibbs RB, Johnson DA.

Brain Res Bull 69(6):660-665, 2006.

It is known that infusion of 192-IgG-SAP (Cat. #IT-01) into the medial septum of rats impairs acquisition of a delayed matching to position (DMP) T-maze task. Here, the authors evaluated whether introduction of an aversive stimulus 30 minutes prior to training would attenuate this deficit. Treated rats received 0.22 µg of 192-IgG-SAP injected into the medial septum. Data indicate that treated rats receiving an intraperitoneal injection of saline 30 minutes prior to training displayed less impairment than rats not receiving the aversive stimulus.

Effect of nucleus basalis magnocellularis cholinergic lesions on fear-like and anxiety-like behavior.

Knox D, Berntson GG.

Behav Neurosci 120(2):307-312, 2006.

Neurons in the nucleus basalis magnocellularis and substantia innominata (NBM/SI) may play a role in mediating some aspects of aversive states. The authors used 0.1 µg injections of 192-IgG-SAP (Cat. #IT-01) into the NBM/SI of rats to investigate the role these neurons play in elevated maze behavior and fear-conditioned behavioral suppression. The lesions did not affect the elevated maze behavior, but behavioral suppression was attenuated. The results indicate that NBM/SI cholinergic neurons are involved in the mediation of anxiety-like states.

Differential responsiveness of dopamine-beta-hydroxylase gene expression to glucoprivation in different catecholamine cell groups.

Li AJ, Wang Q, Ritter S.

Endocrinology 147(7):3428-3434, 2006.

This work examines how subpopulations of hindbrain catecholaminergic neurons participate in systemic glucoregulation. Rats were treated with bilateral 42 ng infusions of anti-DBH-SAP (Cat. #IT-03) into the paraventricular nucleus of the hypothalamus. Dopamine-beta-hydroxylase (DBH) expression in glucoprivic animals was then analyzed by in situ hybridization and immunohistochemistry. The data demonstrate that the ventrolateral medulla contains most of the catecholamine neurons responsive to glucoprivation.

Attenuation of homeostatic responses to hypotension and glucoprivation after destruction of catecholaminergic rostral ventrolateral medulla neurons.

Madden CJ, Stocker SD, Sved AF.

Am J Physiol Regul Integr Comp Physiol 291(3):R751-9, 2006.

C1 neurons in the RVLM express dopamine-beta-hydroxylase (DBH). Anti-DBH-SAP (Cat. #IT-03) was used to eliminate these neurons and examine cardiovascular homeostasis in response to a physiological challenge such as hypotension. 21 ng of anti-DBH-SAP was injected into the RVLM of rats. After food and water had been removed from the cage, the lesioned animals were treated with hydralazine to reduce blood pressure. The results demonstrate that RVLM-C1 cells are involved in responses to homeostatic challenges.

Myeloid precursors and acute myeloid leukemia cells express multiple CD33-related Siglecs.

Nguyen DH, Ball ED, Varki A.

Exp Hematol 34(6):728-735, 2006.

Sialic acid-binding immunoglobulin-like lectins (Siglecs) are a family of cell surface receptors which bind to sialic acid. They are found mainly on leukocytes, and also on acute myeloid leukemia (AML) cells. The authors tested several anti-Siglec antibodies against U937 histiocytic lymphoma cells and THP-1 acute monocytic leukemia cells in vitro. When these antibodies were combined with Mab-ZAP (Cat. #IT-04), a second immunotoxin, the target cells were eliminated. The data suggest that Siglecs may be a viable target for AML therapy.

Suppression of natural killer cell activity by morphine is mediated by the nucleus accumbens shell.

Saurer TB, Carrigan KA, Ijames SG, Lysle DT.

J Neuroimmunol 173(1-2):3-11, 2006.

In this work the authors investigated the role of dopaminergic projections to the nucleus accumbens in modulation of immune parameters such as morphine-induced suppression of splenic natural killer (NK) cell activity. Studies have indicated that acute exposure to opioids decreases NK cell-mediated cytotoxicity. Rats received bilateral 0.5 µg-injections of anti-DAT-SAP (Cat. #IT-25) into the nucleus accumbens shell. Treated animals showed no immunosuppression upon administration of morphine, indicating that dopaminergic neurons in the nucleus accumbens play a major role in this pathway.

Combined damage to entorhinal cortex and cholinergic basal forebrain neurons, two early neurodegenerative features accompanying Alzheimer’s disease: effects on locomotor activity and memory functions in rats.

Traissard N, Herbeaux K, Cosquer B, Jeltsch H, Ferry B, Galani R, Pernon A, Majchrzak M, Cassel JC.

Neuropsychopharmacology 32(4):851-871, 2007.

Two characteristics of Alzheimer’s disease (AD) are cholinergic dysfunction in the basal forebrain, and neuronal damage in the entorhinal cortex. Using 5 µg intracerebroventricular (icv) injections of 192-IgG-SAP (Cat. #IT-01), and 2.3 µg icv injections of OX7-SAP (Cat. #IT-02), locomotor activity, working, and reference memory of rats were examined. Although 192-IgG-SAP lesions caused limited deficits, rats receiving both lesions exhibited several behaviors associated with AD. The authors suggest that combining these lesions may be a more accurate model for AD than 192-IgG-SAP alone.

Descending facilitation from the rostral ventromedial medulla maintains visceral pain in rats with experimental pancreatitis.

Vera-Portocarrero LP, Xie JY, Kowal J, Ossipov MH, King T, Porreca F.

Gastroenterology 130(7):2155-2164, 2006.

Here the authors investigated the role of ascending or descending pathways in the mediation of pain caused by pancreatitis. Rats received 1.5 pmol injections of dermorphin-SAP (Cat. #IT-12) into each side of the rostral ventromedial medulla. Abdominal hypersensitivity was tested using von Frey filaments. Although the ablation of mu-opioid receptor-expressing neurons by dermorphin-SAP did not prevent the initial expression of pancreatitis pain, maintenance of this pain was absent. The data link maintenance of pancreatitis pain to descending pathways.