- Home
- Knowledge Base
- References
Descending noradrenergic control of conditioned pain modulation and postoperative pain trajectory in rats.
Parker RA, Wang F, Hayashida K, Martin TJ, Eisenach JC, Peters CM (2013) Descending noradrenergic control of conditioned pain modulation and postoperative pain trajectory in rats. Neuroscience 2013 Abstracts 461.10. Society for Neuroscience, San Diego, CA.
Summary: Aim of Investigation: Chronic pain after surgery (CPAS) is now recognized as a significant clinical problem that occurs in 10-50% of patients undergoing surgery. Recent clinical studies demonstrate the integrity of endogenous pain inhibitory controls are important for preventing CPAS, however this relationship and underlying mechanisms haven’t been examined in preclinical models. We hypothesized that a causal relationship exists between impaired endogenous analgesia and chronic pain after surgery that is in part dependent on descending noradrenergic pathways. Methods: We examined the integrity of endogenous analgesia in rats preoperatively used a previously described method for assessing conditioned pain modulation (CPM) in rats (Ferrari et al., 2010) involving injection of capsaicin (150μg/50μl) in the forepaw as a conditioning stimulus and detection of hindpaw mechanical thresholds (Randall-Selitto device) as the test stimulus. The partial L5 spinal nerve ligation (pSNL) model and mixed effects growth curve modeling of mechanical withdrawal thresholds assessed for 10 weeks following surgery were used to study resolution of postoperative mechanical hypersensitivity. The role of descending spinal noradrenergic pathways in CPM and postoperative trajectory was assessed by ablating spinal noradrenergic fibers with DβH-saporin or blocking their activity pharmacologically with adrenergic receptor antagonists. Results: Forepaw capsaicin resulted in release of NE in the lumbar spinal cord and this CPM paradigm was partially prevented by spinal idazoxan (30μg, i.t.). CPM assessed preoperatively resulted in pronounced but variable increases in hindpaw mechanical withdrawal thresholds at 30 minutes (range: 60-140g). Within individual rats, we observed a significant correlation between the degree of preoperative CPM and the slope of trajectory (P=0.006, r=0.610) as rats with lower endogenous analgesia had slower resolution of mechanical hypersensitivity. In support of a causal role between endogenous spinal noradrenergic activity and CPAS, depletion of spinal noradrenergic fibers prior to pSNL resulted in a significant reduction in the slope of trajectory within the ipsilateral hindpaw. Conclusions: Collectively, these studies suggest that the ability to engage descending endogenous noradrenergic pathways may be critical in determining whether CPAS develops. Furthermore, the use of growth curve modeling to study CPAS will allow us to examine the ability of socio-environmental conditions or pharmacological interventions to impair or improve aspects of postoperative pain trajectory as part of future studies.
Related Products: Anti-DBH-SAP (Cat. #IT-03)
Neuroprotection with gonadal steroids following partial motoneuron depletion: Dependence on steroid receptor activation and hormone action at the target musculature.
Sengelaub DR, Cai Y, Chung M, Mnayarji (2013) Neuroprotection with gonadal steroids following partial motoneuron depletion: Dependence on steroid receptor activation and hormone action at the target musculature. Neuroscience 2013 Abstracts 467.12. Society for Neuroscience, San Diego, CA.
Summary: Aim of Investigation: Chronic pain after surgery (CPAS) is now recognized as a significant clinical problem that occurs in 10-50% of patients undergoing surgery. Recent clinical studies demonstrate the integrity of endogenous pain inhibitory controls are important for preventing CPAS, however this relationship and underlying mechanisms haven’t been examined in preclinical models. We hypothesized that a causal relationship exists between impaired endogenous analgesia and chronic pain after surgery that is in part dependent on descending noradrenergic pathways. Methods: We examined the integrity of endogenous analgesia in rats preoperatively used a previously described method for assessing conditioned pain modulation (CPM) in rats (Ferrari et al., 2010) involving injection of capsaicin (150μg/50μl) in the forepaw as a conditioning stimulus and detection of hindpaw mechanical thresholds (Randall-Selitto device) as the test stimulus. The partial L5 spinal nerve ligation (pSNL) model and mixed effects growth curve modeling of mechanical withdrawal thresholds assessed for 10 weeks following surgery were used to study resolution of postoperative mechanical hypersensitivity. The role of descending spinal noradrenergic pathways in CPM and postoperative trajectory was assessed by ablating spinal noradrenergic fibers with DβH-saporin or blocking their activity pharmacologically with adrenergic receptor antagonists. Results: Forepaw capsaicin resulted in release of NE in the lumbar spinal cord and this CPM paradigm was partially prevented by spinal idazoxan (30μg, i.t.). CPM assessed preoperatively resulted in pronounced but variable increases in hindpaw mechanical withdrawal thresholds at 30 minutes (range: 60-140g). Within individual rats, we observed a significant correlation between the degree of preoperative CPM and the slope of trajectory (P=0.006, r=0.610) as rats with lower endogenous analgesia had slower resolution of mechanical hypersensitivity. In support of a causal role between endogenous spinal noradrenergic activity and CPAS, depletion of spinal noradrenergic fibers prior to pSNL resulted in a significant reduction in the slope of trajectory within the ipsilateral hindpaw. Conclusions: Collectively, these studies suggest that the ability to engage descending endogenous noradrenergic pathways may be critical in determining whether CPAS develops. Furthermore, the use of growth curve modeling to study CPAS will allow us to examine the ability of socio-environmental conditions or pharmacological interventions to impair or improve aspects of postoperative pain trajectory as part of future studies.
Related Products: Anti-DBH-SAP (Cat. #IT-03)
Hindbrain catecholamine neurons control rapid switching of metabolic substrate use during glucoprivation in male rats.
Li AJ, Wang Q, Dinh TT, Wiater MF, Eskelsen AK, Ritter S (2013) Hindbrain catecholamine neurons control rapid switching of metabolic substrate use during glucoprivation in male rats. Endocrinology 154(12):4570-4579. doi: 10.1210/en.2013-1589
Summary: Previous work has shown that corticosterone secretion in response to glucoprivation is at least in part controlled by hindbrain catecholamine neurons in the paraventricular nucleus of the hypothalamus (PVH). In this work the authors investigate the metabolic consequences of lesioning these neurons. Rats received bilateral 82-ng infusions of Anti-DBH-SAP (Cat. #IT-03) into the PVH. Saporin (Cat. #PR-01) was used as a control. Although lesioned animals had the same energy expenditure and locomotor activity as controls, they also had a higher respiratory exchange ratio, indicating a reduced ability to switch from carbohydrate to fat metabolism in response to glucoprivation.
Related Products: Anti-DBH-SAP (Cat. #IT-03), Saporin (Cat. #PR-01)
A1 noradrenergic neurons lesions reduce natriuresis and hypertensive responses to hypernatremia in rats.
da Silva EF, Freiria-Oliveira AH, Custodio CH, Ghedini PC, Bataus LA, Colombari E, de Castro CH, Colugnati DB, Rosa DA, Cravo SL, Pedrino GR (2013) A1 noradrenergic neurons lesions reduce natriuresis and hypertensive responses to hypernatremia in rats. PLoS One 8(9):e73187. doi: 10.1371/journal.pone.0073187
Summary: Using bilateral 63-ng injections of Anti-DBH-SAP (Cat. #IT-03) into two levels of the caudal ventrolateral medulla, the authors assessed several pressor responses to infusion of hypertonic saline. Saporin (Cat. #PR-01) was used as a control. The results suggest that medullary noradrenergic A1 neurons are involved in the regulation of some responses to acute changes in body fluid composition.
Related Products: Anti-DBH-SAP (Cat. #IT-03), Saporin (Cat. #PR-01)
Implication of cerebral dopamine-beta hydroxylase for cardiovascular and mood regulation in rats.
Chang ST, Liu YP, Huang CL, Wang PY, Tung CS (2013) Implication of cerebral dopamine-beta hydroxylase for cardiovascular and mood regulation in rats. Chin J Physiol 56(4):209-218. doi: 10.4077/CJP.2013.BAB103
Summary: The ascending fibers affected by norepinephrine are involved in a variety of processes, including emotion, anxiety, and regulation of central autonomic outflows such as cardiovascular regulation and energy balance. The authors examined whether the loss of norephinephrine would cause autonomic failure in cardiovascular regulation. Rats received a single intraventricular injection of anti-DBH-SAP (Cat. #IT-03). Saporin (Cat. #PR-01) was used as a control. The results demonstrate that norepinephrine deficits in the brain influence reduction of excitatory responses to orthostatic stress.
Related Products: Anti-DBH-SAP (Cat. #IT-03), Saporin (Cat. #PR-01)
P2Y1 receptors expressed by C1 neurons determine peripheral chemoreceptor modulation of breathing, sympathetic activity, and blood pressure.
Wenker IC, Sobrinho CR, Takakura AC, Mulkey DK, Moreira TS (2013) P2Y1 receptors expressed by C1 neurons determine peripheral chemoreceptor modulation of breathing, sympathetic activity, and blood pressure. Hypertension 62(2):263-273. doi: 10.1161/HYPERTENSIONAHA.113.01487
Summary: Peripheral chemoreceptor activation response is mediated by catecholaminergic C1 cells in the rostral ventrolateral medulla (RVLM). The authors investigated the molecular mechanisms linking this drive to increased sympathetic activity and hypertension through a variety of methods, including lesioning C1 cells in the RVLM. Rats received 4.2-ng bilateral injections of Anti-DBH-SAP (Cat. #IT-03) into the RVLM. Comparison of lesioned animals to controls demonstrated that P2Y1 receptors on C1 cells in the RVLM are key components in the regulation of breathing, sympathetic nerve activity, and blood pressure.
Related Products: Anti-DBH-SAP (Cat. #IT-03)
Sudden death following selective neuronal lesions in the rat nucleus tractus solitarii.
Talman WT, Lin LH (2013) Sudden death following selective neuronal lesions in the rat nucleus tractus solitarii. Auton Neurosci 175(1-2):9-16. doi: 10.1016/j.autneu.2012.11.008
Summary: The nucleus tracts solitarii (NTS) is the terminus of cardiovascular reflex nerves. Early work in this area sought to identify transmitters involved in the control of this region. The authors used SSP-SAP (Cat. #IT-11) and anti-DBH-SAP (Cat. #IT-03) to examine the role of NK-1r-expressing neurons and catecholaminergic neurons in baroreflex control in the NTS. Either 3 ng of SSP-SAP or 42 ng of anti-DBH-SAP was injected into the NTS of rats and baroreflex function was compared 7 days later. Although each toxin had a specific effect in terms of the types of cells eliminated, both toxins initiated a disturbance of the central baroreflex control that led to the death of some animals.
Related Products: SSP-SAP (Cat. #IT-11), Anti-DBH-SAP (Cat. #IT-03)
Yohimbine anxiogenesis in the elevated plus maze requires hindbrain noradrenergic neurons that target the anterior ventrolateral bed nucleus of the stria terminalis.
Zheng H, Rinaman L (2013) Yohimbine anxiogenesis in the elevated plus maze requires hindbrain noradrenergic neurons that target the anterior ventrolateral bed nucleus of the stria terminalis. Eur J Neurosci 37(8):1340-1349. doi: 10.1111/ejn.12123
Summary: The anterior ventrolateral bed nucleus of the stria terminalis (vIBST) appears to be important for increased noradrenergic signaling to trigger anxiety-like behavior. 42.8 ng of anti-DBH-SAP (Cat. #IT-03) was administered to the vIBST of rats in bilateral injections. Elimination of noradrenergic neurons in the vIBST abolished yohimbine-induced anxiogenesis in an elevated plus maze, indicating that hindbrain noradrenergic neurons targeting the vIBST are involved in this mechanism.
Related Products: Anti-DBH-SAP (Cat. #IT-03)
Intact catecholamine inputs to the forebrain are required for appropriate regulation of corticotrophin-releasing hormone and vasopressin gene expression by corticosterone in the rat paraventricular nucleus.
Kaminski KL, Watts AG (2012) Intact catecholamine inputs to the forebrain are required for appropriate regulation of corticotrophin-releasing hormone and vasopressin gene expression by corticosterone in the rat paraventricular nucleus. J Neuroendocrinol 24(12):1517-1526. doi: 10.1111/j.1365-2826.2012.02363.x
Summary: Corticosterone releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVH) control release of adrenocorticotropic hormone and glucocorticoids. In order to determine the contribution of these neurons to CRH and vasopressin expression in the PVH the authors administered bilateral 42 ng injections of anti-DBH-SAP (Cat. #IT-03) into the PVH of both normal and adrenalectomized rats. Mouse IgG-SAP (Cat. #IT-18) was used as a control. The data demonstrate that under certain conditions CRH and vasopressin gene expression is modulated by interactions between corticosterone and catecholaminergic projections to the hypothalamus.
Related Products: Anti-DBH-SAP (Cat. #IT-03), Mouse IgG-SAP (Cat. #IT-18)
Noradrenergic denervation by DBH saporin reduces behavioral responsivity to L-DOPA in the hemi-parkinsonian rat.
Ostock CY, Lindenbach D, Jaunarajs KL, Dupre KB, Goldenberg A, Bhide NS, Bishop C (2012) Noradrenergic denervation by DBH saporin reduces behavioral responsivity to L-DOPA in the hemi-parkinsonian rat. Neuroscience 2012 Abstracts 758.06. Society for Neuroscience, New Orleans, LA.
Summary: Dopamine (DA) replacement therapy with L-DOPA remains the most effective treatment for Parkinson’s disease (PD), but prolonged use frequently leads to deleterious side effects including involuntary choreic and dystonic movements known as L-DOPA induced dyskinesias (LID). It has been well established that DA loss in PD is accompanied by concomitant noradrenergic (NE) denervation of the locus coeruleus (LC); however, the contribution of NE loss to LID remains controversial and is often overlooked in traditional animal models of PD. Previous work from our lab demonstrated that rats with NE depletion induced by the selective NE neurotoxin DA beta hydroxylase saporin (DBH saporin) display reduced behavioral sensitivity to L-DOPA. The current investigation sought to further characterize the utility of DBH saporin lesions in a rodent model of PD by employing immunohistological techniques to correlate NE cell loss with behavioral outcome. Male Spraque-Dawley rats received unilateral 6-OHDA lesions of the medial forebrain bundle with intraventricular injections of either vehicle or DBH saporin. A number of well characterized behavioral tests were employed to determine lesion effects and L-DOPA responsiveness including: the abnormal involuntary movements scale for rodent dyskinesia, the forepaw adjusting steps (FAS) test as a metric of L-DOPA’s anti-parkinsonian efficacy, and locomotor chambers to observe motor performance. Sensitivity of primed animals to different doses of L-DOPA (0-12 mg/kg) and DA agonists SKF81297 (0., 0.08, 0.8 mg/kg) and Quinpirole (0, 0.05, 0.5 mg/kg) was assessed. Reduced behavioral responsiveness was associated with reductions in tyrosine hydroxylase positive cells within the LC of DBH saporin lesioned animals. Results indicate that NE denervation reduced anti-parkinsonian efficacy of L-DOPA on the FAS test. In primed rats, LC NE loss attenuated dyskinetic responses to L-DOPA and the DA agonist SKF81297. Taken together, these results indicate that DBH saporin lesions not only mimick the NE loss seen in idiopathic PD, but also reveal an underexplored contribution of the NE system to the manifestation of PD symptoms and LID.
Related Products: Anti-DBH-SAP (Cat. #IT-03)