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Role of IB4-containing afferents in the effect of IT clonidine
Li X, Bynum T, Hayashida K, Eisenach JC (2005) Role of IB4-containing afferents in the effect of IT clonidine. Neuroscience 2005 Abstracts 171.22. Society for Neuroscience, Washington, DC.
Summary: Alpha2 adrenoceptors diminish pain transmission in animals with normal condition. Our previous data demonstrated clonidine, an Alpha2 adrenoceptor agonist, inhibited calcium influx after an electrical stimulation in the acutely cultured DRG cells from normal animal, 80% of which are Isolectin B4 (IB4) positive. Therefore we assume intrathecal clonidine produces antinociception primarily by actions on IB4-expressing afferents, and clonidine effect will be decreased with the loss of IB4 containing afferents. In the current report, normal rats received an intra-nerve injection of 2 μg of saporin conjugated IB4 (Sap-IB4), a targeted cytotoxin to IB4-expressing neurons, or a 6 μg of saporin as the control in the rat sciatic nerve. Effects of 30 μg intrathecal clonidine were observed for antinociception to thermal and mechanical stimuli in both ipsi- and contra- lateral side to the injection weekly, before and after Sap-IB4 injection for three weeks. Immunocitochemistry study demonstrated that three weeks of Sap-IB4 treatment dramatically decreased IB4 expression in DRG cells or spinal afferent fibers in the ipslateral side. The basal thermal withdrawal latency and mechanical withdrawal threshold were slightly increased by Sap-IB4 in the ipsilateral side one week after injection, which were returned to normal three weeks later. Additionally, the effeccy of 30 μg clonidine for antinociception to thermal and mechanical stimuli was significantly decreased at the end of treatment. These observations suggested IB4 containing afferents may play a very important role in intrathecal clonidine mediated antinociception.
Related Products: IB4-SAP (Cat. #IT-10)
Spinal-supraspinal serotonergic circuits regulating neuropathic pain and its treatment with gabapentin.
Suzuki R, Rahman W, Rygh LJ, Webber M, Hunt SP, Dickenson AH (2005) Spinal-supraspinal serotonergic circuits regulating neuropathic pain and its treatment with gabapentin. Pain 117(3):292-303. doi: 10.1016/j.pain.2005.06.015
Summary: The anticonvulsant, gabapentin, is thought to modulate calcium channel function. In animals, it also affects abnormal pain function. 10 µl of 1 µM SP-SAP (Cat. #IT-07) was injected into the subarachnoid space of rats. It was found that the effects of gabapentin were blocked when NK-1r expressing neurons in the dorsal horn were eliminated. The results suggest that not only is the NK-1r pathway a determinant of neuronal and behavioral manifestations of neuropathy, it is also involved in the action of gabapentin.
Related Products: SP-SAP (Cat. #IT-07)
Ablation of a population of neurons in the dorsal horn of the spinal cord is insufficient to induce sprouting of touch responsive myelinated afferents into the innervation territory of pain sensitive unmyelinated afferents.
Whiteside GT, Woods ME, Pearson MS, Pomonis JD, Turchin PI, Walker K (2005) Ablation of a population of neurons in the dorsal horn of the spinal cord is insufficient to induce sprouting of touch responsive myelinated afferents into the innervation territory of pain sensitive unmyelinated afferents. Med Hypotheses Res 2:275-282.
Related Products: SP-SAP (Cat. #IT-07)
The behavioral and neuroanatomical effects of IB(4)-saporin treatment in rat models of nociceptive and neuropathic pain.
Tarpley JW, Kohler MG, Martin WJ (2004) The behavioral and neuroanatomical effects of IB(4)-saporin treatment in rat models of nociceptive and neuropathic pain. Brain Res 1029(1):65-76. doi: 10.1016/j.brainres.2004.09.027
Summary: Using the fact that primary afferent neurons bind isolectin B4 (IB4), the authors injected 5 µg of IB4-SAP (Cat. #IT-10) into the sciatic nerve in the left thigh. After recovery, these animals were then treated with a L5 spinal nerve ligation. Lesioned animals displayed attenuated NGF-induced hyperalgesia, as well as differences in other pain-model markers. The data indicate that IB4-positive C-fibers play a discrete role in NGF-induced hyperalgesia, as well as in the development of neuropathic pain.
Related Products: IB4-SAP (Cat. #IT-10)
IB4-SAP reduces IB4 staining in the spinal cord and prevents axotomy induced sprouting of Aβ fibers
Pearson MS, Woods M, Whiteside GT, Garrison AE, Pomonis JD, Walker K (2004) IB4-SAP reduces IB4 staining in the spinal cord and prevents axotomy induced sprouting of Aβ fibers. Neuroscience 2004 Abstracts 858.6. Society for Neuroscience, San Diego, CA.
Summary: Peripheral nerve injury results in hyperalgesia and allodynia. It has been proposed that sprouting of myelinated touch responsive Aß-fibers into the innervation territory of pain sensitive C-fibers in the spinal cord contributes to these abnormal behaviors. The extent of sprouting has recently been challenged and it has been proposed that C-fibers rather than Aß-fibers are involved. We have investigated whether selectively ablating a population of small diameter nociceptors using isolectin B4 conjugated to saporin (IB4-SAP), reduces axotomy-induced sprouting. Male Sprague-Dawley rats received intraneural injections of either IB4-SAP or PBS (3 µl, 0.66 µg/µl) and two weeks later the sciatic nerve was axotomized at the mid-thigh level. Two weeks later, the sciatic nerve was injected with the retrograde tracer, cholera toxin-ß subunit (CTB) (2 µl, 2%) that selectively traces Aß-fibers. Three days post CTB the animals were perfused, the spinal cord harvested, sectioned and stained immunohistochemically for IB4 and CTB. IB4-SAP treatment resulted in a substantial reduction of IB4 staining in the spinal cord versus PBS injected controls. As previously described, axotomy resulted in considerable CTB immunostaining in laminae I, II and III compared to non-axotomized controls in which it was present only in laminae I and III. IB4-SAP treatment followed by axotomy resulted in a substantial reduction of CTB immunostaining in lamina II compared to PBS injected controls. These results suggest that intraneural IB4-SAP ablates a population of small diameter nociceptors and that axotomy induced CTB staining in lamina II is due to uptake of CTB by C-fibers.
Related Products: IB4-SAP (Cat. #IT-10)
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Investigation of the functional role of non-peptidergic primary afferent sensory fibres in the transmission of pain related information
Bailey AL, Bennett G, Ribeiro-da-Silva A (2004) Investigation of the functional role of non-peptidergic primary afferent sensory fibres in the transmission of pain related information. Neuroscience 2004 Abstracts 484.1. Society for Neuroscience, San Diego, CA.
Summary: It is well established that small diameter, unmyelinated, primary afferent C-fibres can be divided into two neurochemically defined populations, one that contains neuropeptides such as Substance P (SP) and Calcitonin-gene related peptide (CGRP) and the other which binds Isolectin B4 (IB4) and is relatively peptide negative. A great deal of circumstantial evidence indicates that the non-peptidergic afferents play a functionally distinct role in pain transmission compared to peptidergic afferents. Indeed, the concept of two distinct subpopulations of C-fibres would indicate the occurrence of parallel processing in pain pathways. However, the functional role of non-peptidergic afferents in the transmission of pain-related information is still unclear. In an attempt to clarify their functional role, we decided to study the development of hyperalgesia and allodynia in adult male Sprague-Dawley rats with selective ablation of IB4-binding, non-peptidergic afferent input to the dorsal horn. To achieve this, we injected IB4 conjugated to Saporin (SAP) into the left sciatic nerve and examined both neurochemical and behavioural changes over a month’s time. Our data show that following injection of the toxin conjugate, IB4-labelling, P2X3-immunopositive fibre terminals disappear from a band in the superficial dorsal horn that expands over a two week period until it comprises most of the mediolateral extent of the dorsal horn. Behavioural data indicates that there are transient changes in acute pain thresholds to mechanical and thermal stimuli. Changes in pain thresholds in animals lacking non-peptidergic input into the spinal dorsal horn in an animal model of Complete Freund’s Adjuvant (CFA) induced inflammation will also be presented.
Related Products: IB4-SAP (Cat. #IT-10)
The effects of chronic deafferentation and SSP-saporin on pain responses, spinal cord neurons and on the structure and function of the somatosensory thalamus (VPL) in the macaque monkey
Ralston HJ, Wiley RG, Dougherty PM, Weng HR, Cata J, Chen JH, Hopkins SD, Canchola SA, Galo E, Vierck CJ (2004) The effects of chronic deafferentation and SSP-saporin on pain responses, spinal cord neurons and on the structure and function of the somatosensory thalamus (VPL) in the macaque monkey. Neuroscience 2004 Abstracts 295.1. Society for Neuroscience, San Diego, CA.
Summary: We have used behavioral, physiological and anatomical methods to examine the effects of chronic (> 2 years) lesions of the dorsal column pathway and of the intrathecal administration of the neurotoxin SSP-saporin in adult M. arctoides. Normal animals were evaluated to determine their responses to noxious heat (52 to 58°C) applied to the lower limbs. Subsequently, the monkeys were anesthetized and had unilateral lesions of the dorsal and dorsolateral spinal cord white matter pathways at midthoracic levels. After recovering from the surgery, their pain responses were studied for more than 1 year, following which SSP-saporin was administered to the lumbosacral spinal cord. The animals were found to have a decrease in their responses to noxious heat applied to the lower limbs. Terminal physiological experiments revealed that the neurons within the lower limb representation of VPL on the side contralateral to the thoracic cord lesion did not have normal receptive fields, although some cells responded to stimulation of both upper and lower limbs. Histological sections of lumbar spinal cord were stained for neurokinin 1 receptor (NK-1R) and showed a significant decrease in lamina I NK-1R positive neurons. Electron microscopy of VPL revealed patterns of synaptic terminals that were different than those found in VPL of normal macaques. We will determine whether there is a significant correlation between the altered behaviors and the physiological and anatomical changes in these animals as a consequence of somatosensory deafferentation.
Related Products: SSP-SAP (Cat. #IT-11)
Mu-opioid receptor-expressing neurons in the nucleus reticularis gigantocellularis contribute to descending facilitation during the development of inflammatory pain
Wei F, Zou S, Robbins MT, Ren K, Dubner R (2004) Mu-opioid receptor-expressing neurons in the nucleus reticularis gigantocellularis contribute to descending facilitation during the development of inflammatory pain. Neuroscience 2004 Abstracts 297.3. Society for Neuroscience, San Diego, CA.
Summary: We have previously shown that nucleus reticularis giangocellularis (NGC) is involved in descending facilitation of inflammatory hyperalgesia. The cellular mechanisms of descending facilitation from the NGC are unknown. The targeted destruction of the mu-opioid receptor-containing neurons in the rostral ventromedial medulla (RVM) by a dermorphin-saporin conjugate prevents nerve injury-induced hyperalgesia in rats (Porreca et al., J. Neurosci. 21:5281, 2001). We examined the effects of selective deletion of the mu-opioid receptor-expressing neurons in the sub-regions of RVM on nocifensive behaviors in rats. After microinjection of dermorphin-saporin conjugate (1.5 pmol/500 nl) into the RVM, there were no changes in baseline thermal and mechanical sensitivity to noxious stimuli. However, the injection of dermorphin-saporin conjugate into bilateral NGC (n=7) significantly attenuated the thermal hyperalgesia and mechanical allodynia at 30 min to 1 d after hindpaw inflammation produced by injection of complete Freund’s adjuvant, compared to sham (blank-saporin or dermorphin) groups (n=3-6). The lesion of the nucleus raphe magnus (NRM) (n=3) only slightly reduced hyperalgesia at 3 h after inflammation. The loss of NGC mu-opioid receptor-containing neurons also decreased nocifensive behaviors only in phase II of the formalin model. In contrast, NRM lesions were without an effect on formalin-induced phase I/II responses. These findings indicate that selective deletion of the mu-opioid receptor-containing neurons in the nucleus reticularis giangocellularis attenuates inflammatory hyperagesia and allodynia.
Related Products: Dermorphin-SAP / MOR-SAP (Cat. #IT-12)
Behavioral evidence for a capsaicin-sensitive inhibitory pathway (CSIP): A novel modulatory role for substance P
King CD, Baker B, Gu JG, Vierck CJ, Yezierski RP (2004) Behavioral evidence for a capsaicin-sensitive inhibitory pathway (CSIP): A novel modulatory role for substance P. Neuroscience 2004 Abstracts 292.18. Society for Neuroscience, San Diego, CA.
Summary: Exposure to noxious thermal stimulation or application of capsaicin cream causes the release of SP from capsaicin-sensitive primary afferent terminals that activate neurokinin-1 receptor (NK1R) expressing neurons in the superficial dorsal horn. Recent evidence suggests the existence of a capsaicin-sensitive inhibitory pathway (CSIP), a novel inhibitory mechanism that involves NK1R expressing neurons in laminae III-V. To determine the functional significance of these NK1R expressing neurons, substance P-saporin neurotoxin (SP-SAP) was used to ablate NK1R neurons in the superficial laminae. Elimination of the NK1R neurons in this region made it possible to evaluate the modulatory effects of NK1R expressing inhibitory neurons in deeper laminae. Reflexive responses were evaluated in rats during a 10-minute trial at 44.5°C before (pre-) and 14 days after (post-) intrathecal injection of 350ng SP-SAP. Testing conditions included: 1) baseline; 2) hindpaw application of 1% capsaicin cream; and, 3) intrathecal injection of the NK1 antagonist CP-97,345 following hindpaw application of 1% capsaicin cream. In normal rats, hindpaw application of capsaicin produced thermal hyperalgesia. In contrast, application of capsaicin produced a hypoalgesia in the same rats after treatment with SP-SAP. The capsaicin-induced hyperalgesia in normal rats was blocked by CP-97,345. The antagonist also blocked the capsaicin-induced hypoalgesia in SP-SAP rats. In conclusion, it is suggested that substance P activates inhibitory interneurons in the deep dorsal horn. The inhibitory effect initiated by substance P on pain transmission neurons represents a novel role of substance P in the spinal processing of nociceptive information.
Related Products: SP-SAP (Cat. #IT-07)
Spinal neurons involved in the generation of at-level pain following spinal injury in the rat.
Yezierski RP, Yu CG, Mantyh PW, Vierck CJ, Lappi DA (2004) Spinal neurons involved in the generation of at-level pain following spinal injury in the rat. Neurosci Lett 361(1-3):232-236. doi: 10.1016/j.neulet.2003.12.035
Summary: The elimination of substance P receptor-expressing neurons in lamina I of the spinal cord using SP-SAP (Cat. #IT-07) has been shown to reduce behavior associated with chronic pain. The authors investigated the effects of 150 or 300 ng SP-SAP treatment during or after intraspinal administration of quisqualic acid in rats. Both treatments resulted in a reduction of pain-associated behavior. These results demonstrate that pain following spinal cord injury involves a population of spinal neurons expressing the substance P receptor.
Related Products: SP-SAP (Cat. #IT-07)