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Central sensitization in the trigeminal nucleus caudalis produced by a conjugate of substance P and the A subunit of cholera toxin.
Caudle R, King C, Nolan T, Suckow S, Vierck C, Neubert J (2010) Central sensitization in the trigeminal nucleus caudalis produced by a conjugate of substance P and the A subunit of cholera toxin. J Pain 11:838-846. doi: 10.1016/j.jpain.2010.05.007
Objective: To understand central sensitization.
Summary: Findings suggest that central sensitization leads to activation of an endogenous opioid system. Intracisternal administration of SP-CTA is a useful model for studying central sensitization as a disease process without having to induce a peripheral injury.
Usage: SP-CTA was diluted in PBS and injected in a volume of 10 μl (rats) or 1 μl (mice) over the course of three minutes.
Related Products: SP-CTA (Cat. #IT-39)
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 (2010) Effect of applying p75NTR saporin to a punctured intervertebral disc on calcitonin gene-related peptide expression in rat dorsal root ganglion neurons. J Orthop Sci 15(3):407-413. doi: 10.1007/s00776-010-1469-x
Summary: 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.
Related Products: 192-IgG-SAP (Cat. #IT-01)
Pain is a salient “stressor” that is mediated by corticotropin-releasing factor-1 receptors.
Hummel M, Cummons T, Lu P, Mark L, Harrison JE, Kennedy JD, Whiteside GT (2010) Pain is a salient “stressor” that is mediated by corticotropin-releasing factor-1 receptors. Neuropharmacology 59(3):160-166. doi: 10.1016/j.neuropharm.2010.05.001
Summary: Given that corticotrophin-releasing factor (CRF) plays a major role in the response to stress, the authors investigated the role CRF-1 receptors may play in the perception of pain. Both rats and mice received 10µl intrathecal injections of 10 µM CRF-SAP (Cat. #IT-13) following a spinal nerve ligation. Administration of CRF-SAP attenuated tactile hypersensitivity, indicating that CRF-1 receptors are involved in pain perception.
Related Products: CRF-SAP (Cat. #IT-13)
Synaptic plasticity and pain: role of ionotropic glutamate receptors.
Larsson M, Broman J (2011) Synaptic plasticity and pain: role of ionotropic glutamate receptors. Neuroscientist 17(3):256-73. doi: 10.1177/1073858409349913
Summary: This review discusses the role of glutaminergic sensory synapses in pain hypersensitivity caused by tissue or nerve injury. The focus is on the roles of ionotrophic glutamate receptors, and how they are involved in dorsal horn synaptic plasticity. The role of substance P in such mechanisms is briefly discussed, as elucidated by the use of SP-SAP (Cat. #IT-07).
Related Products: SP-SAP (Cat. #IT-07)
Targeted ablation of mesenteric projecting sympathetic neurons reduces the hemodynamic response to pain in conscious spinal cord transected rats.
Lujan HL, Palani G, Peduzzi J, Dicarlo SE (2010) Targeted ablation of mesenteric projecting sympathetic neurons reduces the hemodynamic response to pain in conscious spinal cord transected rats. Am J Physiol Regul Integr Comp Physiol 298(5):R1358-1365. doi: 10.1152/ajpregu.00755.2009
Summary: Autonomic dysreflexia is a life-threatening hypertension as a result of a spinal cord injury above thoracic level 6. The authors investigated whether reduction of sympathetic activity can reduce the severity of this condition. Rats received 13.5 µg injections of CTB-SAP (Cat. #IT-14) into the celiac ganglion resulting in ablation of mesenteric projecting sympathetic neurons. Lesioned animals displayed a reduced pressor response to pain after spinal cord transection, to some extent ameliorating autonomic dysreflexia.
Related Products: CTB-SAP (Cat. #IT-14)
Role of brainstem noradrenergic neurons in modulation of operant nocifensive responses to heat: Pharmacology and hyperalgesia.
Chatterjee K, Kline IV RH, Wiley RG (2009) Role of brainstem noradrenergic neurons in modulation of operant nocifensive responses to heat: Pharmacology and hyperalgesia. Neuroscience 2009 Abstracts 855.10/X15. Society for Neuroscience, Chicago, IL.
Summary: Many spinal dorsal horn neurons are under direct modulation from various brainstem nuclei which act to modulate nociceptive activity. Nocifensive reflex response modulation by spinally projecting noradrenergic brainstem nuclei has been extensively categorized. Strong evidence supports a role for these neurons in the modulation of reflex nocifensive responses but the role of noradrenergic neurons in the cerebral component of nociception remains to be defined in rats. In the present study, we sought to determine the effects of selectively destroying noradrenergic rostral brainstem neurons (A5,A6,A7) on operant escape from 44°C floor heat under several conditions: 1-baseline (after i.c.v. toxin/vehicle injection), 2- after s.c. injection of morphine, clonidine or yohimbine, 3- three hours after bilateral dorsal hindpaw application of mustard oil (secondary hyperalgesia), and 3- three hours after bilateral plantar application of 0.9% capsaicin cream (primary hyperalgesia). Rats were tested daily until steady operant escape responding (~1 month), then injected i.c.v. with 10µl of PBS (vehicle control, n=8) or antiDBH-saporin (10µg, n=8). After recovery from toxin injection, escape responses decreased in the antiDBH-sap rats. Morphine (0, 0.5, 1.0, 2.0 mg/kg s.c.) 20 min prior to testing, dose dependently attenuated escape from the noxious thermal plate at 44oC for all treatment groups. antiDBH-sap treated rats, however, showed an enhanced morphine effect (more prolonged occupancy of the noxious thermal plate). Three hours after plantar capsaicin, or mustard oil to the dorsal surface of both hindpaws, PBS but not antiDBH-sap rats showed enhanced escape. Systemic clonidine (0.125mg/kg) decreased escape for both PBS and antiDBH-sap treated rats, but the anti-nociceptive effect was greater in antiDBH-sap rats. Systemic yohimbine (1.0, 2.5, 5.0mg/kg) had no effect on escape in antiDBH-sap rats but enhanced escape in PBS rats. In direct contrast to effects on escape responding, antiDBH-sap did not affect hotplate lick/guard initial latencies to nociceptive heat at 44° or 47oC. Escape responses to aversively bright light were also decreased in antiDBH-sap rats suggesting generally decreased responsiveness to aversive stimuli. These results support a significant role for rostral brainstem noradrenergic neurons in modulation of pain and highlight important differences between reflex nocifensive responses (hotplate) and operant (escape) responses.
Related Products: Anti-DBH-SAP (Cat. #IT-03)
Spinal µ-opiate receptor (MOR)-expressing dorsal horn neurons: Role in modulating pain and opiate analgesia.
Kline IV RH, Wiley RG (2009) Spinal µ-opiate receptor (MOR)-expressing dorsal horn neurons: Role in modulating pain and opiate analgesia. Neuroscience 2009 Abstracts 560.13/CC72. Society for Neuroscience, Chicago, IL.
Summary: Selective destruction of MOR-expressing interneurons in lamina II of the dorsal horn of the spinal cord increases reflex nocifensive responses to formalin and decreases the anti-nociceptive effects of morphine on the hotplate and in the formalin test. The interpretation of these studies is limited because reflex-based assays may not accurately reflect the cerebral component of nociception. Therefore, we sought to determine the effects of selectively destroying MOR-expressing dorsal horn neurons on baseline operant responses to aversive thermal and mechanical stimuli in a shuttle box task and effects of systemic morphine and naloxone in the same task. The preference apparatus consisted of a 15 X 15 X 30 cm smoked Plexiglas vented chamber placed upon two adjoining temperature-controlled smooth aluminum floor plates (thermal preference task) or one smooth temperature-controlled floor plate adjoined to a room temperature surface covered with 40 grit sandpaper (mechanical preference task). For both preference tasks, response functions were obtained by pairing a 44°C plate or the sandpaper surface with either 11°, 16°, 25°, 38° or 46°C. Rats were intrathecally injected over the lumbar cord with either 625ng of derm-sap (n=7) or blank-sap (n=6) followed by daily thermal or mechanical preference testing on a randomized schedule. Derm-sap treated rats showed enhanced avoidance of aversive thermal stimuli and the aversive mechanical stimulus. Morphine and naloxone significantly altered responses of control rats (blank-sap), but not derm-sap rats, in both thermal and mechanical preference tasks. We interpret these results as showing that the derm-sap lesion produces hyperalgesia/allodynia, impairs the anti-nociceptive and analgesic effects of morphine and therefore indicating that postsynaptic dorsal horn MOR-expressing neurons play a key role in modulating nociception, pain and opiate analgesia. Dysfunction of these neurons may also play a role in pathological pain states.
Related Products: Dermorphin-SAP / MOR-SAP (Cat. #IT-12)
The role of limbic norepinephrine in cannabinoid-induced aversion.
Carvalho AF, Reyes AS, Van Bockstaele EJ (2009) The role of limbic norepinephrine in cannabinoid-induced aversion. Neuroscience 2009 Abstracts 449.3/V29. Society for Neuroscience, Chicago, IL.
Summary: The endocannabinoid system has been implicated in diverse physiological mechanisms including modulation of pain and analgesia, learning and memory and feeding, among others. Thus, targeting the cannabinoid system has risen to the forefront in the development of novel treatments for a number of pathophysiological processes. Consistent with this, agonists of the cannabinoid receptor type 1 (CB1R) have been successfully used in the treatment of severe anorexia in patients with AIDS and in alleviating nausea and vomiting in patients undergoing chemotherapy. However, significant side effects have been observed in clinical trials raising concerns regarding the potential clinical utility of cannabinoid-based agents. Disturbances in mood and affect, including paranoia, anxiety and nervousness, have been reported in patients. Understanding the neural circuits and neurochemical substrates impacted by cannabinoids will provide a better means of gauging their actions within the central nervous system that contribute to the expression of unwanted side effects. We have previously shown an increase in anxiety-like behaviors in rats receiving repeated administration of cannabinoid agonists. This increase in anxiety was accompanied by increases in indices of noradrenergic activity. In the present study, we investigated whether norepinephrine in the limbic forebrain of rats is required for cannabinoid-induced aversion using an immunotoxin lesion approach combined with behavioral analysis using a place conditioning paradigm. Male Sprague Dawley rats received bilateral injections of a ribosomal toxin, saporin (SAP) conjugated to an antibody that specifically recognizes the enzyme dopamine-beta-hydroxylase (DSAP), into the limbic forebrain. Control rats received saporin alone. As previously reported, administration of the synthetic cannabinoid receptor agonist, WIN 55,212-2 (3.0mg/kg), induced aversion in a place conditioning paradigm in SAP-only treated rats. The rats’ spatial memory was also evaluated using the Morris Water Maze. Depletion of norepinephrine using DSAP in specific limbic regions impaired cannabinoid-induced aversion to WIN 55,212-2 without affecting learning and memory processes. Taken together, noradrenergic projections to the limbic forebrain may be critical in the manifestation of aversive behaviors associated with cannabinoid agonist exposure.
Related Products: Anti-DBH-SAP (Cat. #IT-03)
CCK receptor- expressing dorsal horn neurons: Role in pain and morphine analgesia.
Datta S, Chatterjee K, Kline IV RH, Wiley RG (2009) CCK receptor- expressing dorsal horn neurons: Role in pain and morphine analgesia. Neuroscience 2009 Abstracts 265.13/Z37. Society for Neuroscience, Chicago, IL.
Summary: Spinal intrathecal cholecystokinin (CCK) has anti-opiate activity, and the CCK antagonist, proglumide potentiates opiate analgesia. In the present study, we sought to determine the effects of selectively destroying CCK receptor-expressing lumbar dorsal horn neurons using the targeted cytotoxin, CCK-saporin on reflex and operant nocifensive responses to heat, and on the actions of systemic morphine and naloxone. Exp. 1: Adult, female rats were injected into the lumbar CSF with either 1500 ng of CCK-sap (n=7) or blank (control nonsense peptide)-saporin (n=6). Exp. 2: rats were pre-injected intrathecally with 1 ug of proglumide (CCK antagonist) followed by 1500 ng CCK-sap (n=4) or only CCK-sap (1500 ng; n=4). Rats were then tested on the hotplate at 44°C and 47°C and on an operant thermal preference task (TPT) using a shuttle box where the floor on one side was 15°C and the other 45°C. Morphine was tested in the TPT using 0, 0.5, 1.5 and 2.5 mg/kg s.c. 4-8 weeks post-toxin. Naloxone (0 vs 0.8 mg/kg s.c) was also tested in the TPT. In Exp. 1, the CCK- sap group showed decreased hotplate reflex responses, but decreased time on the 45°C side in the TPT. In Exp. 2, CCK-sap only rats also showed greater heat aversion in the TPT. In both Exps, CCK-sap groups demonstrated greater heat aversion (less analgesia) than either control group after morphine in the TPT. After naloxone, both control groups, but not the CCK-sap rats, showed increased heat aversion (hyperalgesia). We interpret these results as showing that selective destruction of CCK receptor- expressing superficial dorsal horn neurons increases nocifensive reflex responses to aversive heat and produces thermal hyperalgesia while decreasing the effects of both morphine and naloxone suggesting a complex role for CCK receptor-expressing dorsal horn neurons in modulation of nociception and opiate drug action.
Related Products: CCK-SAP (Cat. #IT-31)
Featured Article: Ablation of GRPR+ neurons in the spinal cord by bombesin-saporin knocks out itch sensation in mice without affecting pain circuit
Chen ZF, Sun YG, Zhao ZQ, Meng XL, Yin J, Liu XY (2009) Featured Article: Ablation of GRPR+ neurons in the spinal cord by bombesin-saporin knocks out itch sensation in mice without affecting pain circuit. Targeting Trends 10(4)
Related Products: Bombesin-SAP (Cat. #IT-40), Blank-SAP (Cat. #IT-21)
Read the featured article in Targeting Trends.
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