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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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Time-dependent descending facilitation from the rostral ventromedial medulla maintains, but does not initiate, neuropathic pain.
Burgess SE, Gardell LR, Ossipov MH, Malan Jr TP, Vanderah TW, Lai J, Porreca F (2002) Time-dependent descending facilitation from the rostral ventromedial medulla maintains, but does not initiate, neuropathic pain. J Neurosci 22(12):5129-5136. doi: 10.1523/JNEUROSCI.22-12-05129.2002
Summary: Various indications, such as declining afferent discharge over time, suggest that the mechanisms involved in persistent neuropathic pain are different than those that initiate the pain. The authors have previously shown that cells expressing the mu-opioid receptor are involved in the descending pain pathway. In this work, the authors lesioned the rostral ventromedial medulla (RVM) in rats using 1.5 pmol in 0.5 µl of dermorphin-SAP (Cat. #IT-12) administered to each side of the RVM. Measurements of pain-related behavior show that mu-opioid receptor-expressing cells in the RVM are involved in the maintenance of heightened sensitivity to stimuli seen in neuropathic pain.
Related Products: Dermorphin-SAP / MOR-SAP (Cat. #IT-12)
Dermorphin-saporin conjugate relieves inflammatory pain after peripheral application.
Palecek J, Paleckova V, Willis WD (2001) Dermorphin-saporin conjugate relieves inflammatory pain after peripheral application. Neuroscience 2001 Abstracts 508.10. Society for Neuroscience, San Diego, CA.
Summary: Opioid receptors have been shown to exist in specific population of DRG neurons signaling nociceptive information from peripheral tissues. In our study, we attempted to selectively destroy these neurons by using a peripheral application of the mu opioid agonist Dermorphin conjugated to ribosome inactivating toxin Saporin (DERM-SAP, Advanced Targeting Systems) in order to alleviate inflammatory pain. Intraarticular or intraplantar injection of carrageenan or CFA was used to induce inflammation in rats. The DERM-SAP conjugate was injected into the inflamed area 12-48h later. Responses of the animals to mechanical and thermal stimuli were tested before and after the inflammation and up to 21 days after the DERM-SAP application. The rats developed heat hyperalgesia in the affected paw 24 hours after the intraarticular CFA injection. In the saline injected group the hyperalgesia persisted for up to 19 days, but in the DERM-SAP injected group the signs of hyperalgesia were improving from day 7. Also mechanical allodynia tested with a VF filament (1.1g) was alleviated in the DERM-SAP group. In the carrageenan group, the DERM-SAP treatment decreased the heat hyperalgesia and prevented the development of hyperalgesia after repeated carrageenan application, 21days after the DERM-SAP treatment. Postmortem evaluation with a specific antibody showed presence of saporin in the DRG neurons. Our results show that peripheral application of DERM-SAP relieves inflammatory pain and suggest that peripheral application of neuropeptides conjugated to cell toxins or other substances such as antisense probes could be a useful tool for treating pain of peripheral origin. Supported by NIH grants NS09743 and NS11253.
Related Products: Dermorphin-SAP / MOR-SAP (Cat. #IT-12)
Inhibition of neuropathic pain by selective ablation of brainstem medullary cells expressing the µ-opioid receptor.
Porreca F, Burgess SE, Gardell LR, Vanderah TW, Malan TP Jr, Ossipov MH, Lappi DA, Lai J (2001) Inhibition of neuropathic pain by selective ablation of brainstem medullary cells expressing the µ-opioid receptor. J Neurosci 21(14):5281-5288. doi: 10.1523/JNEUROSCI.21-14-05281.2001
Summary: The presence of descending projections in the pain pathway raises the possibility that abnormal sustained activity may perpetuate chronic pain. Using 3-ng injections of dermorphin-SAP (Cat #IT-12) on either side of the RVM in rats the authors both prevented and reversed neuropathic pain caused by spinal nerve ligation.
Related Products: Dermorphin-SAP / MOR-SAP (Cat. #IT-12)
Featured Article: Dermorphin-SAP kills MOR-positive cells
Lappi DA (2001) Featured Article: Dermorphin-SAP kills MOR-positive cells. Targeting Trends 2(3)
Related Products: Dermorphin-SAP / MOR-SAP (Cat. #IT-12)
Dermorphin-saporin targets tonic descending facilitation in the rostral ventromedial medulla to block and reverse neuropathic pain.
Burgess SE, Vanderah TW, Mantyh PW, Malan Jr TP, Ossipov MH, Lappi D, Lai J, Porreca F (2000) Dermorphin-saporin targets tonic descending facilitation in the rostral ventromedial medulla to block and reverse neuropathic pain. Neuroscience 2000 Abstracts 243.6. Society for Neuroscience, New Orleans, LA.
Summary: The hypothesis that chronic pain from L5/L6 spinal nerve ligation (SNL) is due to tonic activation of descending pain facilitation mechanisms was explored by selective targeting mu (μ) opioid receptor expressing cells in the RVM (i.e., presumably, ON cells). Rats were treated with a single RVM injection of dermorphin (DERM)(μ agonist), saporin (SAP), or dermorphin-saporin conjugate (DERM-SAP) and responses to non-noxious (von Frey filaments) or noxious (Hargreave’s test) stimuli characterized. DERM-SAP retained high affinity for μ receptors and acutely produced antinociception (tail-flick test), indicating agonist actions of the conjugate. Decreased staining of μ receptor-expressing cells was seen in superficial dorsal horn and in dorsal root ganglia 28 days after intrathecal injection of DERM-SAP, but not DERM or SAP. RVM DERM-SAP, DERM or SAP did not significantly alter baseline thresholds to von Frey filaments or noxious heat applied to the paw over 28 days. At day 28, RVM pretreated rats were subjected to sham- or SNL surgery and responses to tactile and heat stimuli monitored 7 days later (i.e., 35 days after the RVM pretreatment). DERM and SAP pretreated SNL rats showed the expected development of tactile allodynia and thermal hyperalgesia, while DERM-SAP pretreated rats did not. The RVM pretreatments did not alter responses in sham-operated controls. Administration of RVM DERM-SAP, but not SAP or DERM, to SNL rats showed full reversal of established allodynia/hyperalgesia by day 14. RVM pretreatment with β-funaltrexamine (β-FNA; opioid μ antagonist) prevented the antiallodynic and antihyperalgesic effects of subsequent DERM-SAP injection. These data, together with findings of blockade of SNL pain with RVM lidocaine or lesions of the dorsolateral funiculus, support the possibility of tonic activation of descending facilitation as a basis for chronic neuropathic pain.
Related Products: Dermorphin-SAP / MOR-SAP (Cat. #IT-12)
Intrathecal dermorphin-saporin decreases morphine effect in hotplate algesia testing.
Miller SA, Lappi DA, Wiley RG (2000) Intrathecal dermorphin-saporin decreases morphine effect in hotplate algesia testing. Neuroscience 2000 Abstracts 212.8. Society for Neuroscience, New Orleans, LA.
Summary: The targeted cytotoxin, dermorphin-saporin, selectively destroys cells expressing MOR. In the present study, we gave dermorphin-saporin by lumbar i.t. injection and sought to determine if destroying dorsal horn neurons expressing MOR would alter thermal sensitivity and/or response to systemic morphine (MS) using hotplate testing under various conditions. 16 male Sprague-Dawley rats were tested on constant temperature (0.3, 44 and 47 C) and incremental (0.1 C/sec from 28 to 57 C) hotplates. Then 8 rats received lumbar intrathecal injections of derm-sap (465 ng) and 8 received vehicle using a subarachnoid PE-10 catheter that was removed 10 mins after injection. Retesting rats after toxin/vehicle injection showed no change in responses to any of the hotplate conditions. However, vehicle but not derm-sap rats showed increased lick latency on the incremental hotplate 20 mins after MS, 2.5 mg/kg, s.c. At 5 mg/kg of MS, vehicle and dermorphin-saporin rats showed identical responses. Capsaicin cream (0.94%) applied to the plantar surface of both hindpaws 3 hrs before testing on the 44 C hotplate produced decreased lick latencies in both groups of rats. MS, 5 mg/kg, s.c., produced increased lick latencies in capsaicin treated vehicle but not derm-sap rats. At 10 mg/kg, MS produced identical effects in capsaicin treated vehicle and toxin rats. These results indicate that i.t. derm-sap produced no change in baseline thermal sensitivity but did diminish the effect of low dose MS under conditions that preferentially test C nociceptor function suggesting that MOR-expressing dorsal horn neurons play a role in the analgesic action of low dose MS.
Related Products: Dermorphin-SAP / MOR-SAP (Cat. #IT-12)
Entering through the doors of perception: characterization of a highly selective Substance P receptor-targeted toxin.
Lappi DA, Wiley RG (2000) Entering through the doors of perception: characterization of a highly selective Substance P receptor-targeted toxin. Neuropeptides 34(5):323-328. doi: 10.1054/npep.2000.0827
Related Products: Dermorphin-SAP / MOR-SAP (Cat. #IT-12)
Synthesis and receptor binding analysis of dermorphin hepta-, hexa- and pentapeptides.
Attila M, Salvadori S, Balboni G, Bryant SD, Lazarus LH (1993) Synthesis and receptor binding analysis of dermorphin hepta-, hexa- and pentapeptides. Int J Pept Prot Res 42:550-559. doi: 10.1111/j.1399-3011.1993.tb00363.x
Related Products: Dermorphin-SAP / MOR-SAP (Cat. #IT-12)
Amino acid composition and sequence of dermorphin, a novel opiate-like peptide from the skin of Phyllomedusa sauvagei.
Montecucchi PC, de Castiglione R, Piani S, Gozzini L, Erspamer V (1981) Amino acid composition and sequence of dermorphin, a novel opiate-like peptide from the skin of Phyllomedusa sauvagei. Int J Pept Prot Res 17(3):275-283. doi: 10.1111/j.1399-3011.1981.tb01993.x
Related Products: Dermorphin-SAP / MOR-SAP (Cat. #IT-12)