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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)
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)
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)
Spinal noradrenergic activation mediates allodynia reduction from an allosteric adenosine modulator in a rat model of neuropathic pain.
Li X, Conklin D, Ma W, Zhu X, Eisenach JC (2002) Spinal noradrenergic activation mediates allodynia reduction from an allosteric adenosine modulator in a rat model of neuropathic pain. Pain 97:117-125. doi: 10.1016/s0304-3959(02)00011-8
Summary: T62 is a thiobene compound that enhances adenosine agonist binding to the A1 receptor. Activation of the adenosine receptor has been effective in several different pain models. The authors used a spinal nerve ligation model for mechanical allodynia to assess T62 efficacy and mode of action. Rats treated with anti-DBH-SAP (4 µg in 5 µl, Cat. #IT-03) experienced no anti-allodynia effects from T62 administration, indicating that modulation of mechanical allodynia by T62 utilizes the spinal noradrenergic system.
Related Products: Anti-DBH-SAP (Cat. #IT-03)
Dose-dependent effects of intrathecal substance P-saporin and SSP-saporin.
Wiley RG, Kline IV RH, Lappi DA (2001) Dose-dependent effects of intrathecal substance P-saporin and SSP-saporin. Neuroscience 2001 Abstracts 281.11. Society for Neuroscience, San Diego, CA.
Summary: Selective destruction of lamina I dorsal horn neurons expressing the neurokinin-1 receptor (NK-1R) can attenuate responses to capsaicin injection and thermal hyperalgesia/mechanical allodynia in models of inflammatory, persistent or neuropathic pain. In the present study, we sought to determine the relationships between spinal intrathecal dose of substance P-saporin or the related toxin, SSP-saporin, the loss of NK-1R neurons and reduction of phase II formalin responses. Rats were injected intrathecally with 10 ul of either vehicle, 175 ng, 350 ng or 700 ng of SP-sap. Others were injected with either vehicle, 25 ng, 50 ng or 100 ng of SSP-sap. After 2 weeks, nocifensive behavior was scored for 90 min after a unilateral hindpaw injection of dilute formaldehyde. The amount of phase II nocifensive behavior from 20-90 min post injection was totaled for each animal. Rats were sacrificed and transverse lumbosacral spinal cord sections were stained for NK-1R using indirect immunoperoxidase technique. Digital micrographs of the superficial dorsal horn were captured and the number of pixels in the darkest intensity values were expressed as percent of the analysis area for each dorsal horn. Significant correlations were noted for dose vs dark pixel percentage and for dark pixel percentage vs phase II formalin behavior. The greater the toxin dose the greater the loss of NK-1R staining and the greater the attenuation of phase II formalin behavior. These results indicate that the toxin effects on pain behavior are proportional to the degree of loss of lamina I NK-1R expressing neurons.
Related Products: SSP-SAP (Cat. #IT-11)
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)
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)