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Depletion of spinal norepinephrine increases the duration of postoperative pain related behaviors following acute plantar incision and partial nerve injury in the rat.
Wang F, Eisenach JC, Peters CM (2012) Depletion of spinal norepinephrine increases the duration of postoperative pain related behaviors following acute plantar incision and partial nerve injury in the rat. Neuroscience 2012 Abstracts 785.11. Society for Neuroscience, New Orleans, LA.
Summary: Background and Objective: The percentage of patients that develop chronic postsurgical pain can range from 10-50% depending on the type of surgery. The underlying mechanisms responsible for the transition from an acute to chronic postoperative pain state are unknown. Recent clinical studies suggest that the integrity of endogenous pain inhibitory circuits may be important for preventing this transition. The descending noradrenergic transmission has well-known inhibitory effects on spinal synaptic transmission and norepinephrine has anti-inflammatory effects on spinal glial activation. We hypothesized that disrupting spinal noradrenergic fibers in rats prior to peripheral tissue injury would enhance spinal glial activity and impair resolution of postoperative pain. Methods: To test this hypothesis, we used a model of acute pain (Brennan incision model) and a model of nerve injury involving partial L5 spinal nerve ligation. We intrathecally injected dopamine β hydroxylase conjugated to the ribosomal toxin saporin (DβH-sap, 5 μg) or control (IgG-sap) to Sprague-Dawley rats 14 days prior to surgery to deplete noradrenergic fibers. Sensitivity to mechanical stimuli (von Frey) and spontaneous guarding were assessed for several weeks. We used immunohistochemistry to assess microglial (IBA1) and astrocyte (GFAP) activation in spinal cord tissue. Results: Depletion of noradrenergic fibers resulted in a significant increase in the duration of mechanical hypersensitivity in the ipsilateral paw of rats with plantar incision (6 days in IgG-sap treated rats vs. at least 21 days in DβH-sap treated rats) and partial L5 spinal nerve ligation (42 days in IgG-sap treated rats vs. at least 70 days in DβH-sap treated rats). Depletion of noradrenergic fibers did not affect mechanical withdrawal thresholds in normal rats suggesting both tissue injury and spinal noradrenergic depletion were required for prolonged mechanical hypersensitivity. The duration of spontaneous guarding following plantar incision was not affected by DβH-sap treatment. Additionally, microglia and astrocyte activation was increased in the spinal cord 21 days following incision and 70 days after nerve injury in DβH-sap treated rats compared to IgG-sap treated rats. Conclusions: These findings highlight the crucial role of spinally projecting noradrenergic pathway in the resolution of incision and nerve injury induced hypersensitivity which may be due in part to inhibitory effect of norepinephrine on spinal glial activation. Future studies will focus on the adrenergic receptor subtypes and mechanisms responsible for the transition from acute to chronic postoperative pain in these models.
Related Products: Anti-DBH-SAP (Cat. #IT-03)
Selective damage to glia in the nucleus tractus solitarii attenuates cardiovascular reflexes.
Talman WT, Jones S, Nitschke Dragon D, Lin L-H (2012) Selective damage to glia in the nucleus tractus solitarii attenuates cardiovascular reflexes. Neuroscience 2012 Abstracts 524.05. Society for Neuroscience, New Orleans, LA.
Summary: Lesions of the nucleus tractus solitarii (NTS) are known to attenuate or abolish cardiovascular reflex responses. We have previously reported that lesions produced by saporin (SAP) conjugates and focused on neurons that express the neurokinin-1 (NK1) receptor or on other neurons that express both tyrosine hydroxylase (TH) and dopamine-β-hydroxylase (DBH), also attenuate baroreflex function in rats. We found that lesions of both types of neurons also led to loss of glia that stained with glial fibrillary acidic protein (GFAP). Further, we found that injection of SAP alone into the NTS led to loss of GFAP staining while leaving neurons in the region unaffected. Because both of the lesions directed at neurons were made by a toxic conjugate containing SAP, we sought to determine if SAP alone produced changes in cardiovascular reflex function. We found that injection of SAP (3 ng in 100 nl) into the NTS led to loss of the glial marker GFAP as well as connexin 43 (Cx43) immunofluorescent labeling in the NTS but did not affect the neuronal markers NMDAR1 (NMDA receptor subunit 1), GluR2 (AMPA receptor subunit 2), neuronal nitric oxide synthase (nNOS), TH, DBH, vesicular glutamate transporters (VGluTs), choline acetyl transferase (ChAT), NK1, and protein gene product 9.5 (PGP 9.5). In animals treated with bilateral injections of SAP into the NTS, reflex responses were decreased during testing of the baroreflex, the chemoreflex, or the von Bezold Jarisch reflex. Comparable decreases in baroreflex responses were seen in animals treated with SAP alone when compared with other animals treated with SAP conjugates that targeted and concentrated damage to TH/DBH neurons or NK1 neurons in NTS. In contrast, when TH/DBH neurons were targeted by the toxin 6-hydroxydopamine (6-OHDA) lability of arterial pressure did not occur as it did in the other SAP and SAP conjugate studies and reflex responses to the activation of the baroreflex, the chemoreflex, and the von Bezold Jarisch reflex did not differ from control. Furthermore, injections containing SAP or a SAP conjugate, but not those containing 6-OHDA, led to lability of arterial pressure as well as cardiac arrhythmias and cardiac myocytolysis. Our studies cannot exclude a physiological effect of SAP on neurons nor can it exclude an indirect effect of glial damage on NTS neurons. However, the similarity of responses when glia seem to have been targeted alone in contrast to those responses when select neuronal types seem to have been targeted suggests that each of the cardiovascular reflexes relies on intact glia in the NTS for full reflex expression.
Related Products: Anti-DBH-SAP (Cat. #IT-03), SSP-SAP (Cat. #IT-11)
Knockdown of noradrenergic locus coeruleus (LC) neurons alleviates chronic orofacial pain
Kaushal R, Ma F, Zhang L, Bright CR, Taylor BK, Westlund KN (2012) Knockdown of noradrenergic locus coeruleus (LC) neurons alleviates chronic orofacial pain. Neuroscience 2012 Abstracts 164.19. Society for Neuroscience, New Orleans, LA.
Summary: Trigeminal neuralgia (TN) is an excruciating and debilitating form of clinical orofacial pain. Noradrenergic locus coeruleus (LC, pontine A6 neurons) is involved in bidirectional modulation of pain. Multiple studies indicate that LC activity is increased during noxious stimulation and following inflammation or nerve damage. Predominantly known for its role in the feedback inhibition of pain, emerging studies also indicate a contribution of the LC in pain facilitation. For example, lesions of the LC significantly reduce tonic behavioral responses to intraplantar formalin injection, prevent autotomy, and reduce hypersensitivity associated with peripheral nerve injury. In this study we hypothesized that noradrenergic (LC) neurons contribute to the facilitation of chronic pain in TN. We used a rat model of TN involving infraorbital nerve chronic constriction injury (ION-CCI) which produces mechanical hypersensitivity as assessed by a reduction in von Frey threshold. Administration of anti-dopamine-β-hydroxylase saporin (anti-DβH-saporin) toxin was performed for selective elimination of noradrenergic LC neurons or IgG saporin (nonspecific) as the control either by intracerebroventricular (i.c.v space 2) or by bilateral spinal trigeminal nucleus (STN) injections. Under minimal restraint, rats received either no stimulation or repeated stimulation with either a 2 or 15-gm von Frey hair applied directly to the maxillary branch. Withdrawal threshold (tactile allodynia) from von Frey fiber stimulation to the face was not changed as compared to baseline in animals subjected to sham surgery; this was true in both saporin and anti-DβH-saporin groups. However, i.c.v. anti-DβH-saporin significantly increased withdrawal threshold animals with ION-CCI as compared to IgG saporin controls. More selective destruction of the LC-trigeminal pathway with bilateral STN anti-DβH-saporin injection also alleviated behavioral signs of chronic orofacial hyperalgesia. Elimination of noradrenergic LC neurons was confirmed by complete loss of tyrosine hydroxylase (TH) immunoreactivity in anti-DβH-saporin injected animals. Compared to unstimulated controls, mechanical stimulation increased immunoreactive phosphorylated extracellular cell-regulated protein kinase (pERK), a marker of neuronal activity, in the LC and STN. Nerve injury also increased expression of a neuronal injury and stress marker, activating transcription factor 3 (ATF3), in trigeminal ganglia neurons. Together, these results indicate that noradrenergic locus coeruleus neurons facilitate chronic orofacial neuropathic pain.
Related Products: Anti-DBH-SAP (Cat. #IT-03)
Catecholaminergic neurons in the ventrolateral medulla are differentially activated by the rate of fall in blood glucose during hypoglycemia, and are required for the rate-dependent hypoglycemic activation of sympathoadrenal responses.
Jokiaho A, Donovan C, Watts A (2012) Catecholaminergic neurons in the ventrolateral medulla are differentially activated by the rate of fall in blood glucose during hypoglycemia, and are required for the rate-dependent hypoglycemic activation of sympathoadrenal responses. Neuroscience 2012 Abstracts 93.05. Society for Neuroscience, New Orleans, LA.
Summary: Hypoglycemic counterregulation is mediated by glucosensors located in the hypothalamus, hindbrain, and portal-mesenteric veins (PV). We have previously shown that when hypoglycemia develops slowly PV glucose sensing is critical for both the sympathoadrenal response and hindbrain Fos activation. Hindbrain catecholaminergic (CA) neurons provide extensive inputs to the hypothalamus and are key participants in the control of energy homeostasis and in the responses to glycemic challenges. However, the role of the various CA cell groups together with the organization of the circuitry between peripheral and central glucose sensing units and the effectors that mediate counterregulatory response to hypoglycemia are unknown. To investigate the role of CA neurons in this network we use hyperinsulinemic-hypoglycemic clamps to induce fast (20mins)- or slow (75min)-onset hypoglycemia in male Wistar rats with saporin/anti-dopamine β-hydroxylase (DBH) DSAP immunotoxin lesions. The hypothalamic paraventricular nucleus (PVH) was injected bilaterally with DSAP or saporin conjugated to mouse IgG (SAP) as controls. PVH DSAP lesions remove about 80% of the DBH-ir and PNMT-ir cell bodies in the ventrolateral medulla. We found that hypothalamic CA afferents are required for sympathoadrenal (epinephrine and nor-epinephrine) responses to slow- but not fast-onset hypoglycemia. We also found robust Fos activation in CA neurons in the ventrolateral (A1, C1) and the dorsomedial medulla, particularly in the nucleus of the solitary tract (NTS; A2, C2). In rats with intact forebrain CA innervations, fast-onset hypoglycemia led to significantly greater DBH/Fos colocalization in the A1, A1/C1 and C1 regions compared to slow-onset hypoglycemia. We further identified substantial numbers of Fos-positive nuclei colocalized in adrenergic neurons (phenylethanolamine-N-methyltransferase (PNMT)) in the A1/C1 and C1 regions, and again these numbers were greater in fast-onset compared to slow-onset hypoglycemia. In SAP and DSAP animals, slow- and fast -onset hypoglycemia led to robust Fos expression in the area postrema and medial parts of the NTS. However, in these two regions there was virtually no Fos and DBH/PNMT-ir colocalization showing that AP and NTS neurons activated following hypoglycemia are not CA. The mechanisms that process the sensory information responsible for sympathoadrenal counterregulatory responses to fast- and slow-onset hypoglycemia are clearly different. We now show that different rates of hypoglycemia onset engage distinct CA cell groups, which in turn differentially participate in rate-dependent counterregulatory responses.
Related Products: Anti-DBH-SAP (Cat. #IT-03)
Lateral and fourth ventricular phloridzin injections stimulate feeding but do not produce hyperglycemia.
Li A-J, Wang Q, Smith BR, Ritter S (2012) Lateral and fourth ventricular phloridzin injections stimulate feeding but do not produce hyperglycemia. Neuroscience 2012 Abstracts 93.18. Society for Neuroscience, New Orleans, LA.
Summary: Sodium-coupled glucose transporters (SGLTs) are a family of glucose transporter found in small intestine, kidney, brain capillaries and some neurons. Because SGLTs are membrane receptors, they interact with extracellular glucose in a metabolism-independent manner. Early work using the SGLT inhibitor, phlorizin, suggested that fourth ventricular phlorizin injection increased feeding, but not blood glucose (Flynn FW and Grill HJ, 1985). To further examine this finding, we injected phloridzin, a competitive inhibitor for SGLT-1 and SGLT-2 into the lateral ventricle (LV) or the 4th ventricle (4V) in rats, and the effects of the injections on food intake and blood glucose were examined. We found that both LV and 4V injections of phloridzin enhanced food intake in rats and that LV and 4V injections were of similar potency. In contrast, neither injection elevated blood glucose levels in the present experiments. We also found that enhancement of feeding by 4V phloridzin was abolished by medial hypothalamic injections of anti-dopamine beta hydroxylase saporin, a retrogradely transported catecholamine immunotoxin that selectively lesions norepinephrine and epinephrine neurons that innervate the injection site. Taken together, these results suggest that SGLT receptors in the brain constitute a novel, nonmetabolic, glucose sensing mechanism that contribute to control of food intake.
Related Products: Anti-DBH-SAP (Cat. #IT-03)
Nucleus of the solitary tract catecholaminergic neurons modulate the cardiovascular response to psychological stress in rats.
Daubert DL, McCowan M, Erdos B, Scheuer DA (2012) Nucleus of the solitary tract catecholaminergic neurons modulate the cardiovascular response to psychological stress in rats. J Physiol 590(Pt 19):4881-4895. doi: 10.1113/jphysiol.2012.232314
Summary: It has been proposed that the nucleus of the solitary tract (NTS) is highly involved in cardiovascular regulation. In light of the fact that catecholaminergic neurons in the NTS are part of stress-related neurocircuitry, the authors investigated whether these neurons attenuate blood pressure increases due to stress. Rats received 22 ng bilateral injections of anti-DBH-SAP (Cat. #IT-03) into the NTS. Mean arterial pressure and baseline plasma epinephrine were measured in a restraint test. Animals lesioned with anti-DBH-SAP displayed a significantly enhanced mean arterial pressure, and reduced plasma epinephrine. These data suggest that catecholaminergic neurons in the NTS inhibit the arterial pressure response to stress, but maintain the corticosteroid response.
Related Products: Anti-DBH-SAP (Cat. #IT-03)
Control of sleep and wakefulness.
Brown RE, Basheer R, McKenna JT, Strecker RE, McCarley RW (2012) Control of sleep and wakefulness. Physiol Rev 92(3):1087-1187 . doi: 10.1152/physrev.00032.2011
Summary: This review summarizes mechanisms in the brain that control sleep and wakefulness. Areas discussed include wakefulness promoting systems, non-REM sleep and REM sleep definitions, the function of each kind of sleep, and dysfunction that occurs as a result of sleep disruption. Several targeted conjugates are mentioned, such as 192-IgG-SAP (Cat. #IT-01), anti-DBH-SAP (Cat. #IT-03), and orexin-SAP (Cat. #IT-20). The review summarizes the use of these products to better understand sleep networks.
Related Products: 192-IgG-SAP (Cat. #IT-01), Anti-DBH-SAP (Cat. #IT-03), Orexin-B-SAP (Cat. #IT-20)
Effects of noradrenergic alpha-2 receptor antagonism or noradrenergic lesions in the ventral bed nucleus of the stria terminalis and medial preoptic area on maternal care in female rats.
Smith CD, Holschbach MA, Olsewicz J, Lonstein JS (2012) Effects of noradrenergic alpha-2 receptor antagonism or noradrenergic lesions in the ventral bed nucleus of the stria terminalis and medial preoptic area on maternal care in female rats. Psychopharmacology (Berl) 224(2):263-276. doi: 10.1007/s00213-012-2749-2
Summary: The authors investigated the function of norepinephrine in mothering. Lesioned animals received 55-ng infusions of anti-DBH-SAP (Cat. #IT-03) into the ventral bed nucleus of the stria terminalis. Mouse-IgG-SAP (Cat. #IT-18) was used as a control. The results demonstrate that downregulated noradrenergic activity is necessary for postpartum maternal behavior, but is not enough to elicit maternal behavior in nulliparous females.
Related Products: Anti-DBH-SAP (Cat. #IT-03), Mouse IgG-SAP (Cat. #IT-18)
A2 noradrenergic lesions prevent renal sympathoinhibition induced by hypernatremia in rats.
Pedrino GR, Freiria-Oliveira AH, Almeida Colombari DS, Rosa DA, Cravo SL (2012) A2 noradrenergic lesions prevent renal sympathoinhibition induced by hypernatremia in rats. PLoS One 7(5):e37587. doi: 10.1371/journal.pone.0037587
Summary: It is thought that renal sympathetic nerve activity is a key component of the response to acute or chronic elevated concentrations of saline in the blood stream. The authors investigated what neurons are involved in the central control of these responses. Rats received bilateral 6.3 ng injections of anti-DBH-SAP (Cat. #IT-03) into the nucleus of the solitary tract. An equimolar amount (1.3 ng) of saporin (Cat. #PR-01) was used as a control. Loss of the A2 noradrenergic neurons altered the renal sympathetic nerve activity response to elevated saline, suggesting that these neurons help regulate the extracellular fluid compartment.
Related Products: Anti-DBH-SAP (Cat. #IT-03), Saporin (Cat. #PR-01)
Sudden death and myocardial lesions after damage to catecholamine neurons of the nucleus tractus solitarii in rat.
Talman WT, Dragon DN, Jones SY, Moore SA, Lin LH (2012) Sudden death and myocardial lesions after damage to catecholamine neurons of the nucleus tractus solitarii in rat. Cell Mol Neurobiol 32(7):1119-1126. doi: 10.1007/s10571-012-9835-1
Summary: Previous work has shown that elimination of neurons expressing the neurokinin-1 receptor (NK1r) from the nucleus tractus solitarii (NTS) causes various circulatory system dysfunctions, often leading to sudden death. The authors injected the brainstem of rats with 42 ng anti-DBH-SAP (Cat. #IT-03). to eliminate catecholaminergic neurons in the NTS that express tyrosine hydroxylase. This elimination had similar cardiac and cardiovascular effects to the elimination of NK1r-expressing neurons.
Related Products: Anti-DBH-SAP (Cat. #IT-03)