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Dermorphin-saporin targets descending facilitation in the rostral ventromedial medulla (rvm) to block CCK-induced abnormal pain
Burgess SE, Gardell LR, Xie Y, Ossipov MH, Vanderah TW, Malan TP, Porreca F, Lai J (2002) Dermorphin-saporin targets descending facilitation in the rostral ventromedial medulla (rvm) to block CCK-induced abnormal pain. Neuroscience 2002 Abstracts 351.11. Society for Neuroscience, Orlando, FL.
Summary: Abnormal pain from L5/L6 spinal nerve ligation (SNL) has been shown to require a time-dependent activation of descending facilitatory pathways arising in the RVM. Additionally, RVM microinjection of L365,260, a cholecystokinin (CCKB) receptor antagonist, reverses SNL-induced tactile and thermal hyperalgesia. These observations suggest the possibility that RVM CCK might “drive” such facilitation from the RVM by activating the endogenous descending facilitation system. Rats were treated with a single RVM injection of dermorphin (DERM) (μ opioid agonist), unconjugated saporin (SAP), or dermorphin-saporin (DERM-SAP) and responses to non-noxious tactile (von Frey filaments) or noxious radiant heat stimuli applied to the hindpaw were measured before and after RVM microinjection of CCK to uninjured rats. RVM DERM-SAP, DERM or SAP did not significantly alter baseline sensory thresholds over 28 days post-injection. At day 28, the rats received bilateral microinjections of CCK (30ng) in the RVM. Rats pretreated with DERM or SAP showed a time-related and revsersible CCK-induced tactile and thermal hypersensitivity. In contrast, RVM CCK failed to produce changes in sensory threshold in animals pretreated with DERM-SAP. The RVM pretreatments did not alter responses in control rats challenged with CCK vehicle. Additionally, lesions of the dorsolateral funiculus also blocked RVM CCK-induced tactile and thermal hypersensitivity. These data support the possibility of CCK-mediated activation of descending facilitation from the RVM as a mechanism of neuropathic pain.
Related Products: Dermorphin-SAP / MOR-SAP (Cat. #IT-12)
Changes in rostral ventromedial medulla (RVM) neurons after the selective loss of mu-opioid receptor expressing cells.
Meng ID, Harasawa I, Lai J, Porreca F, Fields HL (2002) Changes in rostral ventromedial medulla (RVM) neurons after the selective loss of mu-opioid receptor expressing cells. Neuroscience 2002 Abstracts 351.9. Society for Neuroscience, Orlando, FL.
Summary: Different subpopulations of RVM neurons inhibit or facilitate dorsal horn nociceptive transmission. Microinjection of saporin conjugated to the mu-opioid receptor (MOR) agonist dermorphin (derm-sap) into the RVM selectively ablates MOR expressing neurons and diminishes neuropathic pain symptoms (Porreca et al., 2001). We examined the properties of neurons surviving a single RVM injection of derm-sap or sap control. Three classes of RVM neurons (On, Off, and Neutral) have been described with distinct responses to noxious stimuli and MOR agonists. On-cells increase and Off-cells cease firing just prior to a tail flick; MOR agonists inhibit On-cells and disinhibit Off-cells. Neutral cells are unaffected by either noxious stimulation or MOR agonists. Using single unit recording in lightly anesthetized rats a total of 10 electrode tracks were made per rat and each unit encountered was characterized according to its tail flick related activity. Injection of derm-sap (n=8) resulted in fewer On- and Off-cells when compared to saporin controls (n=8). The number of Neutral cells remained unchanged. In separate experiments, after derm-sap pretreatment RVM injections of the MOR agonist DAMGO were ineffective whereas injections of the glutamate receptor agonist homocysteic acid into the same sites increased tail flick latencies. The decrease in number of On-cells after derm-sap is consistent with evidence that these neurons express MOR and facilitate nociceptive transmission. The decrease in number of Off-cells indicates that inhibitory neurons responsible for producing the Off-cell tail flick related pause also express MOR.
Related Products: Dermorphin-SAP / MOR-SAP (Cat. #IT-12)
Enhanced morphine analgeisa after spinal dermorphin-saporin
Miller SA, Lappi DA, Wiley RG (2002) Enhanced morphine analgeisa after spinal dermorphin-saporin. Neuroscience 2002 Abstracts 218.1. Society for Neuroscience, Orlando, FL.
Summary: Dermorphin-saporin (derm-sap) is a neuropeptide toxin conjugate which is selective for neurons expressing the mu-opiate receptor (MOR). The dermorphin moiety of the conjugate binds MOR which is then internalized by the neuron, carrying the toxin with it. The saproin moiety inactivates ribosomes resulting in cell death. In the present study we sought to determine the effect of destroying MOR expressing neurons in Lamina II of the spinal cord dorsal horn on baseline thermal pain sensitivity and response to systemic morphine analgesia. 456 ng derm-sap (n=8) and vehicle (n=8) were injected into the lumbar CSF of adult male Sprague Dawley rats using a subarachnoid catheter inserted through the atlanto-occipital membrane and passed cadually to the level of the lumbar enlargement. 10 minutes following toxin injection, the catheters were withdrawn and the animals allowed to recover. When tested on a hotplate at 52C and on tail-flick assay, toxin rats did not differ from rats injected with vehicle. However, the dose-response curves for subcutaneous morphine were significantly shifted to the left (increased potency) in the toxin treated rats when compared with vehicle controls. Histological analysis of multiple dorsal root ganglia failed to reveal evidence of any primary afferent cell loss. We interpreted these findings to indicate that the neurons destroyed by derm-sap are lamina II MOR expressing neurons and play a role in morphine analgesia at high stimulus intensities.
Related Products: Dermorphin-SAP / MOR-SAP (Cat. #IT-12)
Spinal neurons that possess the substance P receptor are required for the development of central sensitization.
Khasabov SG, Rogers SD, Ghilardi JR, Peters CM, Mantyh PW, Simone DA (2002) Spinal neurons that possess the substance P receptor are required for the development of central sensitization. J Neurosci 22(20):9086-9098. doi: 10.1523/JNEUROSCI.22-20-09086.2002
Summary: Using 5 x 10-5 M intrathecal injections of SP-SAP (Cat. #IT-07) the authors examined the role of SPR-expressing neurons in modulation of pain and hyperalgesia. Treated animals exhibited highly attenuated sensitization to stimuli after capsaicin treatment as compared to controls, but normal responses in the absence of capsaicin
Related Products: SP-SAP (Cat. #IT-07)
Role of lamina I neurons expressing the substance P receptor in the prevention and treatment of a spontaneous pain-like behavior following excitotoxic spinal cord injury (SCI).
Yezierski RP, Yu C, Lappi DA, Mantyh PW, Wiley RG (2002) Role of lamina I neurons expressing the substance P receptor in the prevention and treatment of a spontaneous pain-like behavior following excitotoxic spinal cord injury (SCI). IASP 2002 Abstracts International Association for the Study of Pain, San Diego, CA.
Related Products: SSP-SAP (Cat. #IT-11)
Descending facilitation from the rostral ventromedial medulla maintains, but does not initiate, neuropathic pain.
Burgess SE, Gardell LR, Ossipov MH, Malan T, Vanderah TW, Lai J, Porreca F (2002) Descending facilitation from the rostral ventromedial medulla maintains, but does not initiate, neuropathic pain. IASP 2002 Abstracts International Association for the Study of Pain, San Diego, CA.
Related Products: Dermorphin-SAP / MOR-SAP (Cat. #IT-12)
Loss of IB4-positive sensory neurons mitigates the consequences of nerve injury in the rat.
Tarpley JW, MacIntyre E, Martin WJ (2002) Loss of IB4-positive sensory neurons mitigates the consequences of nerve injury in the rat. IASP 2002 Abstracts International Association for the Study of Pain, San Diego, CA.
Related Products: IB4-SAP (Cat. #IT-10)
Plasticity of wide dynamic range neurones following site-selective ablation of NK-1 receptor expressing lamina I neurones in rat spinal cord.
Suzuki R, Morcuende S, Webber M, Hunt SP, Dickenson AH (2002) Plasticity of wide dynamic range neurones following site-selective ablation of NK-1 receptor expressing lamina I neurones in rat spinal cord. IASP 2002 Abstracts International Association for the Study of Pain, San Diego, CA.
Related Products: SP-SAP (Cat. #IT-07)
Loss of IB4 staining in dorsal root ganglion neurons after spinal nerve ligation is not the result of cell death.
Arunkumar R, Ackerman LL, Jones III R, Holdsworth R, Proudfit HK, Hammond DL (2002) Loss of IB4 staining in dorsal root ganglion neurons after spinal nerve ligation is not the result of cell death. IASP 2002 Abstracts International Association for the Study of Pain, San Diego, CA.
Related Products: IB4-SAP (Cat. #IT-10)
Chronic pain and medullary descending facilitation
Porreca F, Ossipov MH, Gebhart GF (2002) Chronic pain and medullary descending facilitation. Trends Neurosci 25(6):319-325. doi: 10.1016/s0166-2236(02)02157-4
Objective: To examine the likelihood that sustained activation of descending modulatory pathways that facilitate pain transmission could underlie some states of chronic pain.
Summary: Rats treated with Dermorphin-SAP, either before or after spinal nerve ligation injury, did not display neuropathic pain behaviors, although normal nociceptive responses were intact.
Usage: Rostroventromedial medulla (RVM) injected with Dermorphin-SAP.
Related Products: Dermorphin-SAP / MOR-SAP (Cat. #IT-12)
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