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The role of descending facilitation in the initiation and maintenance of mechanical hypersensitivity following inflammation
Carr F, Géranton SM, Hunt SP (2011) The role of descending facilitation in the initiation and maintenance of mechanical hypersensitivity following inflammation. Neuroscience 2011 Abstracts 702.10. Society for Neuroscience, Washington, DC.
Summary: Central sensitisation is the key mechanism involved in the generation of mechanical hypersensitivity associated with tissue injury. Dorsal horn excitability is subject to regulation by descending modulation via the rostral ventromedial medulla (RVM) and enhanced descending facilitation under conditions of persistent nociceptive input contributes to the maintenance of mechanical hypersensitivity in chronic pain states. Depletion of mu-opioid receptor expressing (MOR+) cells of the RVM and depletion of spinal serotonin have been used previously to demonstrate the contribution of descending facilitation to the maintenance of neuropathic pain. Here we have used the same ablation techniques to investigate the contribution of descending pathways to the initiation and maintenance of mechanical hypersensitivity associated with ankle joint inflammation. Male Sprague-Dawley rats (215-220g at the time of injection) received bilateral microinjections of the selective cytotoxin dermorphin-saporin (1.5pM each side). 28 days later the animals received either an injection of 10μl Complete Freund’s Adjuvant (CFA) to the left ankle joint or underwent a sham procedure. Mechanical hypersensitivity of the hindpaw plantar surface was assessed using von Frey hairs from 2 hours up to 8 days post CFA injection. In a separate group of rats (160-180g at the time of injection) depletion of spinal serotonin was out carried out by intrathecal administration of 5,7-dihydroxytrptamine (5,7-DHT). Animals received either 10 μl of 5,7-DHT in saline (6μg/μl) or vehicle control. 6 days later animals received either CFA injection or underwent a sham procedure and mechanical hypersensitivity was assessed as in the dermorphin-saporin experiment. Depletion of the MOR+ cells of the RVM and of spinal serotonin was confirmed using immunohistochemistry. Dermoprhin-saporin pre-treatment resulted in significantly increased paw withdrawal thresholds from 6 hours up to 8 days following CFA injection (p < 0.01, ANOVA with repeated measures). In contrast depletion of spinal serotonin by 5,7-DHT led to a smaller attenuation of mechanical hypersensitivity at 24 hours and 48 hours following inflammation (LSD post hoc test, p < 0.01) but did not result in significantly increased paw withdrawal thresholds at the earlier time points.
Related Products: Dermorphin-SAP / MOR-SAP (Cat. #IT-12)
Transmission of neuropathic pain by spinal neurons expressing the NPY Y1 receptor
Donahue RR, Corder GF, Mcnamara KC, Wiley RG, Taylor BK (2011) Transmission of neuropathic pain by spinal neurons expressing the NPY Y1 receptor. Neuroscience 2011 Abstracts 179.16. Society for Neuroscience, Washington, DC.
Summary: Endogenous neuropeptide Y (NPY) acts at Y receptors in the dorsal spinal cord to exert a tonic inhibitory control of chronic allodynia (Solway et al, PNAS 108:7224-9, 2011). In this and the adjacent presentation, we tested the hypothesis that NPY does this by inhibiting Y1 receptors on pain transmission neurons or on central terminals of primary afferent neurons. We selectively lesioned cells expressing the NPY receptors in the dorsal horn with intrathecal administration of the NPY-conjugated ribosomal toxin, NPY-saporin. NPY-saporin significantly reduced the population of Y1 receptors in the lumbar dorsal horn by over 50%. Neither NK1 receptors in the dorsal horn, nor neuronal counts in the DRG were affected, suggesting a specific effect on Y1+, NK1- neurons in the dorsal horn, while sparing Y1+ central presynaptic terminals. Fourteen days later, we ligated the tibial and common peroneal branches of the sciatic nerve (spared nerve injury, SNI), and evaluated the development of allodynia and hyperalgesia on post-SNI days 1, 3, 5, 7, 14, 21, 28, 35, and 42. When compared to saporin controls, NPY-saporin (1000 ng) decreased mechanical allodynia (von Frey threshold), cold allodynia (paw withdrawal response to application of a drop of acetone) and mechanical hyperalgesia (paw response to blunt pin). This effect began three days after SNI and lasted until forty two days after SNI. When injected in uninjured rats, NPY-saporin did not disrupt motor coordination (accelerating rotarod), baseline heat or mechanical thresholds, or animal activity levels. We conclude that Y1-expressing cells in the dorsal horn exert a tonic facilitatory control of neuropathic pain, and partially mediate the inhibitory actions of NPY.
Related Products: NPY-SAP (Cat. #IT-28)
Activation of postsynaptic NPY Y1 and presynaptic Y2 receptors reduce spinal nociceptive transmission
Corder GF, Donahue R, Winter MK, Chen W, Mccarson KE, Marvizon J, Taylor B (2011) Activation of postsynaptic NPY Y1 and presynaptic Y2 receptors reduce spinal nociceptive transmission. Neuroscience 2011 Abstracts 179.17. Society for Neuroscience, Washington, DC.
Summary: Exogenous (Intondi et al, Neuroscience, 2008) and endogenous (Solway et al, PNAS 108:7224-9, 2011) neuropeptide Y (NPY) acts at Y1 and Y2 receptors in the dorsal horn (DH) to inhibit hypersensitivity to mechanical and thermal stimuli. The adjacent poster (Donahue, et al, SFN 2011) describes our use of a targeted NPY-saporin neurotoxin approach to selectively remove spinal cord (SC) neurons expressing the Y1 receptor — the data implicate a contribution of Y1-expressing, pain transmission neurons to behavioral signs of persistent pain. To determine whether persistent noxious input is associated with a compensatory increase in NPY-mediated inhibitory signaling (presumably at Y1-expressing DH neurons), we performed GTPγS binding assays in SC slices taken from animals following the intraplantar (i.pl) injection of complete Freund’s adjuvant (CFA). CFA significantly reduced the EC50 of Y1 agonist (Leu31,Pro34-NPY)-induced [35S]GTPγS binding in ipsilateral DH to 0.24 ± 0.17 μM, as compared to sham (1.38 ± 0.51 μM). This support the hypothesis that injury increases in the efficiency of coupling between Y1-receptors and G-proteins. To determine whether compensatory NPY inhibition occurs at presynaptic sites, we studied the activity of presynaptic Y2 receptor in NPY-saporin-treated rats. Intrathecal injection of the Y2 receptor antagonist BIIE0246 reduced von Frey thresholds (saporin group from 1.3±0.4 to 0.6 ±0.1g; 750 ng NPY-saporin group from 5.4±1.0 to 1.2±0.2g, p<0.05), suggesting that presynaptic Y2 receptors contribute to a tonic endogenous inhibition of inflammatory pain. In support of this hypothesis, BIIE0246-induced hyperalgesia (21 days after CFA) significantly increased the Emax of Y2 agonist (PYY3-36)-induced [35S]GTPγS binding. We next determined whether NPY acts at presynaptic terminals of primary afferent neurons to reduce the release of substance P (SP). First, in both the i.pl carrageenan and CFA models of inflammatory pain, intrathecal administration of NPY reduced in vivo neurokin-1 (NK1) receptor internalization (an indirect measure of functional SP release). Second, application of either (Leu31,Pro34)-NPY) or PYY3-36 to spinal cord slices concentration-dependently reduced NK1 internalization in the ipsilateral dorsal horn evoked by electrical stimulation of the dorsal root (1000 pulses of 20 V, 0.4 ms at 100 Hz); these effects were reversed by the Y1 antagonist BIBO3304. We conclude that injury up-regulates post-synaptic Y1 and pre-synaptic Y2 spinal inhibitory mechanisms to reduce behavioral signs of persistent pain.
Related Products: NPY-SAP (Cat. #IT-28)
Unidirectional cross-activation of GRPR by MOR1D uncouples itch and analgesia induced by opioids.
Liu XY, Liu ZC, Sun YG, Ross M, Kim S, Tsai FF, Li QF, Jeffry J, Kim JY, Loh HH, Chen ZF (2011) Unidirectional cross-activation of GRPR by MOR1D uncouples itch and analgesia induced by opioids. Cell 147(2):447-458. doi: 10.1016/j.cell.2011.08.043
Summary: Recent work has begun to define the different pathways used by itch and pain. This study was designed to investigate whether opioids cause the itch sensation by gastrin releasing peptide receptor activation. Mice received intrathecal injections of bombesin-SAP (Cat. #IT-40) in order to investigate the coexpression of various signaling molecules in the spinal cord. Blank-SAP (Cat. #IT-21) was used as a control. The data suggest that opioid-induced itch is independent of opioid analgesia, and is controlled through a mu-opioid receptor isoform.
Related Products: Bombesin-SAP (Cat. #IT-40), Blank-SAP (Cat. #IT-21)
Featured Article: Contribution of afferent pathways to nerve injury-induced spontaneous pain and evoked hypersensitivity
King T, Porreca F (2011) Featured Article: Contribution of afferent pathways to nerve injury-induced spontaneous pain and evoked hypersensitivity. Targeting Trends 12(4)
Related Products: SSP-SAP (Cat. #IT-11), Blank-SAP (Cat. #IT-21)
Read the featured article in Targeting Trends.
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Galanin receptor-expressing dorsal horn neurons: role in nociception
Lemons LL, Wiley RG (2011) Galanin receptor-expressing dorsal horn neurons: role in nociception. Neuropeptides 45(6):377-383. doi: 10.1016/j.npep.2011.08.002
Summary: This work examines the mociceptive role of galanin receptor-1-expressing neurons found in the superficial dorsal horn. 500 ng of galanin-SAP (Cat. #IT-34) was injected into the lumbar intrathecal space of rats; blank-SAP (Cat. #IT-21) was used as a control. The rats were then tested in a series of thermal nociception models. Lesioned animals were less sensitive to heat, suggesting that loss of the gal1r-expressing excitatory interneurons disrupted the pain transmission pathway.
Related Products: Galanin-SAP (Cat. #IT-34), Blank-SAP (Cat. #IT-21)
Itch signaling in the nervous system.
Jeffry J, Kim S, Chen ZF (2011) Itch signaling in the nervous system. Physiology (Bethesda) 26(4):286-92. doi: 10.1152/physiol.00007.2011
Summary: This review examines recent work done to elucidate the molecular mechanisms behind the sensation of itch. The progress of mouse genetics has allowed the field to move beyond clinical and physiological studies, toward a better understanding of the signaling involved in nonhistaminergic itch. One study discussed used bombesin-SAP (Cat. #IT-40) in mice to ablate GRPR-positive neurons in the dorsal horn. This lesion reduced scratching in response to pruritogens, but did not affect pain behavior‚ indicating that pain and itch use entirely different pathways.
Related Products: Bombesin-SAP (Cat. #IT-40)
Contribution of afferent pathways to nerve injury-induced spontaneous pain and evoked hypersensitivity.
King T, Qu C, Okun A, Mercado R, Ren J, Brion T, Lai J, Porreca F (2011) Contribution of afferent pathways to nerve injury-induced spontaneous pain and evoked hypersensitivity. Pain 152(9):1997-2005. doi: 10.1016/j.pain.2011.04.020
Summary: Whether exaggerated pain response to a normally innocuous tactile stimulus should be defined as allodynia has been debated. Through the use of several techniques, one of which was intrathecal injection of SSP-SAP (Cat. #IT-11, 16.5 pg), the authors examined which pathways were utilized in this type of pain. Blank-SAP (Cat. #IT-21) was used as a control. The data indicate that tactile stimulation may reflect a different pain state than allodynia.
Related Products: SSP-SAP (Cat. #IT-11), Blank-SAP (Cat. #IT-21)
The effects of intrathecal and systemic gabapentin on spinal substance P release.
Takasusuki T, Yaksh TL (2011) The effects of intrathecal and systemic gabapentin on spinal substance P release. Anesth Analg 112(4):971-976. doi: 10.1213/ANE.0b013e31820f2a16 PMID: 21385982
Summary: Intrathecal or systemically-administered gabapentin is an antihyperalgesic. Given that gabapentin binds a voltage-sensitive calcium channel and that some of these channels regulate substance P (SP) release, the authors investigated whether gabapentin affects SP levels. Immunohistochemistry was done in rats following a gabapentin/formalin pain model. A neurokinin-1 receptor antibody (Cat. #AB-N04) was used to quantitate NK1r, and therefore assess SP activity. It was found that both spinal and systemic gabapentin inhibit SP release from small, primary afferents.
Related Products: Antibody to NK-1 Receptor (Cat. #AB-N04)
Defining the role of norepinephrine in cannabinoid-induced aversion and anxiety
Carvalho AF, Van Bockstaele E (2010) Defining the role of norepinephrine in cannabinoid-induced aversion and anxiety. Neuroscience 2010 Abstracts 833.3. Society for Neuroscience, San Diego, CA.
Summary: In the central nervous system, cannabinoids have been shown to regulate neurotransmitter release, control the hypothalamic-pituitary-adrenal axis and impact several physiological systems, such as food intake, pain and emotion perception. Manipulation of the cannabinoid system using exogenous compounds has been explored as a potential therapeutic for several disorders; however some severe side effects have been reported. 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 may contribute to the expression of unwanted side effects. Previous work from our lab had shown that the cannabinoid receptor (CBr) agonist WIN 55,212-2 is able to induce changes in noradrenergic transmission in limbic structures such as prefrontal cortex (PFC) and the nucleus accumbens (Acb). Moreover, we have previously reported that norepinephrine in the nucleus accumbens (Acb) is critical for WIN 55,212-2-induced aversion, as measured by the place conditioning paradigm. In the present study, we further explore the role of norepinephrine in cannabinoid-induced behaviors. More specifically, we investigate whether norepinephrine in the limbic forebrain of rats is important for the anxiety induced by WIN 55,212-2 (3.0 mg/kg, i.p.). Lesion of noradrenergic neurons in the Acb and bed nucleus of the stria terminalis (BNST) was achieved by the intracerebral injection of the toxin saporin conjugated with an antibody that recognizes the enzyme dopamine-beta-hydroxylase (DBH). This toxin yields a specific lesion of noradrenergic neurons. The anxiogenic effects of WIN 55,212-2 were then measured in the elevated zero maze. The results show that depletion of noradrenergic innervation of the Acb and BNST did not reduce the anxiogenic properties of WIN 55,212-2. These results, together with our previous findings, suggest that the anxiogenic and aversive properties of the CBr agonist WIN 55,212-2 are differentially regulated, with the aversive effects being dependent on noradrenergic transmission within the Acb and the anxiogenic effects being regulated by a, yet to be determined, alternative mechanism/circuit.
Related Products: Anti-DBH-SAP (Cat. #IT-03)