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Disruption of spinal noradrenergic activation delays recovery of acute incision-induced hypersensitivity and increases spinal glial activation in the rat.
Arora V, Morado-Urbina C, Aschenbrenner C, Hayashida K, Wang F, Martin T, Eisenach J, Peters C (2016) Disruption of spinal noradrenergic activation delays recovery of acute incision-induced hypersensitivity and increases spinal glial activation in the rat. J Pain 17:190-202. doi: 10.1016/j.jpain.2015.10.009
Summary: A significant percentage of patients who undergo surgery experience prolonged clinically impactful pain, reducing the quality of life and physical function. Disruption of the descending noradrenergic input has been hypothesized to be important to the generation of this type of pain state. Using an acute incision model, the authors administered 5 μg ofAnti-DBH-SAP (Cat. #IT-03) to the L5-L6 interspace of rats. Mouse IgG-SAP (Cat. #IT-18) was used as a control. Lesioned animals demonstrated a significant increase in mechanical hypersensitivity, and a smaller increase in thermal hypersensitivity. This and other results suggest that spinally projecting noradrenergic pathways are necessary for normal recovery from surgical incision, and possibly other types of pain.
Related Products: Anti-DBH-SAP (Cat. #IT-03), Mouse IgG-SAP (Cat. #IT-18)
Gate control of mechanical itch by a subpopulation of spinal cord interneurons.
Bourane S, Duan B, Koch S, Dalet A, Britz O, Garcia-Campmany L, Kim E, Cheng L, Ghosh A, Ma Q, Goulding M (2015) Gate control of mechanical itch by a subpopulation of spinal cord interneurons. Science 350:550-554. doi: 10.1126/science.aac8653
Summary: Light mechanical stimulation of the hairy skin can induce a form of itch known as mechanical itch. This itch sensation is normally suppressed by inputs from mechanoreceptors, however, in many forms of chronic itch, including alloknesis, this gating mechanism is lost. Scientists demonstrated that a population of spinal inhibitory interneurons (INs), that are defined by the expression of neuropeptide Y::Cre (NPY::Cre), act to gate mechanical itch. Mice in which dorsal NPY::Cre-derived neurons are selectively ablated or silenced develop mechanical itch without an increase in sensitivity to chemical itch or pain. This chronic itch state is histamine-independent and is transmitted independently of the GRP-GRPR signaling pathway. The scientists thereby revealed a dedicated spinal cord inhibitory pathway that gates the transmission of mechanical itch. Mice were given an intrathecal injection of 400 ng of Bombesin-SAP (Cat. #IT-40) in 10 ml of sterile saline to ablate GRPR-expressing neurons.
Related Products: Bombesin-SAP (Cat. #IT-40)
Nociceptive effects of neurotensin(NTS)- and somatostatin(SST)-toxin conjugates applied to the lumbar dorsal horn in rats
Wiley RG (2015) Nociceptive effects of neurotensin(NTS)- and somatostatin(SST)-toxin conjugates applied to the lumbar dorsal horn in rats. Neuroscience 2015 Abstracts 418.11/O12. Society for Neuroscience, Chicago IL.
Summary: Intrathecal injections of NTS or SST have been reported to be anti-nociceptive, and in the case of SST, analgesic in humans. Preliminary experiments in our lab previously showed that lumbar intrathecal injection of the excitatory neuropeptide, NTS, or the inhibitory neuropeptide, SST, conjugated to the ribosome inactivating protein, saporin (sap), produced compulsive scratching/biting of hindquarters resulting in loss of fur and skin. This was thought likely due to pain and/or itching from selective loss of superficial dorsal horn nociceptive inhibitory interneurons expressing NTS receptors. Subsequent experiments using lumbar intrathecal injections of NTS-cholera toxin A chain conjugate resulted in prolonged anti-nociception on hotplate, tail flick and von Frey testing, that was not reversed by naloxone and lasted several days, likely due to sustained activation of the same neurons. The present study sought to determine if the lesions produced by NTS-sap or SST-sap alter nociceptive responses. In the present study, rats, under isoflurane anesthesia, were injected intrathecally using temporarily-placed subarachnoid catheters over the lumbar enlargement with 10 ul of sterile preservative-free normal saline containing either 300-400 ng of NTS-sap, 1 ug of SST-sap or 1 ug blank-sap (control) from Advanced Targeting Systems, San Diego, CA. Catheters were flushed with an additional 10 ul of saline. After post-surgical recovery, the rats were then observed for scratching/biting their hindquarters, nocifensive responses on the hotplate, von Frey mechanical probing of the hindpaws, and on operant thermal escape. 4 of 11 NTS-saporin rats and 5 of 9 SST-saporin rats, but none of 9 blank-saporin rats began scratching within 8-47 days after toxin conjugate injection. Hotplate nocifensive reflex testing at 44.5°C and 47°C showed no significant difference between the groups. Von Frey, operant thermal escape testing and anatomic studies are in progress to further specify the functional effects of the toxin conjugate injections and to identify the dorsal horn neurons being destroyed. The results to date are interpreted as consistent with a possibly unique role for NTS and/or SST receptor-expressing superficial dorsal horn inhibitory interneurons in nociception and/or itch. Excitatory/activating moieties such as cholera toxin A subunit targeted by conjugation to NTS or SST may offer a novel approach to enhance inhibition in nociceptive dorsal horn neurons and to produce analgesia by a non-opioid mechanism.
Related Products: Neurotensin-CTA (Cat. #IT-60), Neurotensin-SAP (Cat. #IT-56), Blank-SAP (Cat. #IT-21), Custom Conjugates
Pain from intra-articular NGF or joint injury in the rat requires contributions from peptidergic joint afferents.
Kras J, Weisshaar C, Pall P, Winkelstein B (2015) Pain from intra-articular NGF or joint injury in the rat requires contributions from peptidergic joint afferents. Neurosci Lett 604:193-198. doi: 10.1016/j.neulet.2015.07.043
Summary: Both peptidergic and non-peptidergic neurons innervate the facet joint, which is the source of pain in a majority of neck trauma. In this work the authors examined these subpopulations of neurons to determine the contribution of each in facet joint pain. 100 ng of SSP-SAP (Cat. #IT-11) was injected into bilateral C6/C7 facet joints of rats. Alternatively, rats received 5 μg of rIB4-SAP (Cat. #IT-10) via the same method. Saporin (Cat. #PR-01) was used as control. SSP-SAP, but not rIB4-SAP was able to prevent NGF-induced mechanical and thermal hypersensitivity. SSP-SAP administration also prevented behavioral hypersensitivity and NGF upregulation in the dorsal root ganglion after facet joint distraction. The data indicate that interference with peptidergic signaling within the facet joint may be a treatment for pain originating in that location.
Related Products: SSP-SAP (Cat. #IT-11), IB4-SAP (Cat. #IT-10), Saporin (Cat. #PR-01)
Limited changes in spinal lamina I dorsal horn neurons following the cytotoxic ablation of non-peptidergic C-fibers.
Saeed A, Pawlowski S, Ribeiro-da-Silva A (2015) Limited changes in spinal lamina I dorsal horn neurons following the cytotoxic ablation of non-peptidergic C-fibers. Mol Pain 11:54. doi: 10.1186/s12990-015-0060-z
Summary: For the most part nociceptive information is moved from the periphery to the spinal cord through small diameter primary afferents. One subclass of these afferents is further divided into peptidergic and non-peptidergic populations. The authors examined the role of the non-peptidergic afferents in normal nociception and pain, especially the aspect that in rat neuropathic and inflammatory pain models there is novel expression of neurokinin-1 receptors in some neurons normally devoid of this protein. Rats received 4.8-μg injections of rIB4-SAP (Cat. #IT-10) into the left sciatic nerve, over three injection sites. While the number of non-peptidergic neurons was significantly reduced, de novo expression of the neurokinin-1 receptor was not increased in lamina I pyramidal projection neurons.
Related Products: IB4-SAP (Cat. #IT-10)
Repeated mu-opioid exposure induces a novel form of the hyperalgesic priming model for transition to chronic pain.
Araldi D, Ferrari L, Levine J (2015) Repeated mu-opioid exposure induces a novel form of the hyperalgesic priming model for transition to chronic pain. J Neurosci 35:12502-12517. doi: 10.1523/JNEUROSCI.1673-15.2015
Summary: Repeated administration of mu-opioid receptor agonists can lead to persistent mechanical hyperalgesia. One current hypothesis is that a form of hyperalgesic priming is triggered by the repeated activation of these receptors. Classic hyperalgesic priming is associated with signaling via protein kinase Cε (PKε), which is mediated by isolectin-B4+ (IB4) nociceptors. In this work the authors eliminated the IB4+ nociceptors with a 3.2 μg intrathecal injection of recombinant IB4-SAP (Cat. #IT-10). The authors found that hyperalgesic priming induced through the use of DAMGO was dependent on protein kinase A activation rather than activation of PKε. This work demonstrates a novel model for hyperalgesic priming transitioning to chronic pain.
Related Products: IB4-SAP (Cat. #IT-10)
Selective elimination of isolectin B4-binding trigeminal neurons enhanced formalin-induced nocifensive behavior in the upper lip of rats and c-Fos expression in the trigeminal subnucleus caudalis.
Oyamaguchi A, Abe T, Sugiyo S, Niwa H, Takemura M (2016) Selective elimination of isolectin B4-binding trigeminal neurons enhanced formalin-induced nocifensive behavior in the upper lip of rats and c-Fos expression in the trigeminal subnucleus caudalis. Neurosci Res 103:40-47. doi: 10.1016/j.neures.2015.07.007
Summary: In adult rats non-peptidergic neurons and peptidergic neurons innervate different areas and layers of the lamina. It is thought that these two neuronal populations play different roles in nociceptive processing, but the specific function of each group is not well understood. In order to investigate peptidergic and non-peptidergic neurons in orofacial pain processing the authors injected the cisterna magna of rats with 2.9 μg of rIB4-SAP (Cat. #IT-10). Blank-SAP (Cat. #IT-21) was used as a control. The lesioned animals displayed more frequent face-rubbing responses on the administration of formalin, indicating that IB4-binding neurons in the trigeminal nerve play an anti-nociceptive role in response to this type of pain.
Related Products: IB4-SAP (Cat. #IT-10), Blank-SAP (Cat. #IT-21)
A central role for spinal dorsal horn neurons that express neurokinin-1 receptors in chronic itch.
Akiyama T, Nguyen T, Curtis E, Nishida K, Devireddy J, Delahanty J, Carstens M, Carstens E (2015) A central role for spinal dorsal horn neurons that express neurokinin-1 receptors in chronic itch. Pain 156:1240-1246. doi: 10.1097/j.pain.0000000000000172
Summary: Chronic itch is caused by increased sensitivity of itch-signaling pathways. It can be generated by normally itchy stimuli (hyperknesis) and by normally non-itchy light touch (alloknesis). The authors used an ovalbumin-induced atopic dermatitis model to study chronic itch in mice. The mice received 400-ng intrathecal injections of Bombesin-SAP (Cat. #IT-40), SSP-SAP (Cat. #IT-11), or the control Blank-SAP (Cat. #IT-21). While Bombesin-SAP significantly attenuated hyperknesis, it had no effect on spontaneous scratching or alloknesis. SSP-SAP reduced all behavioral signs of chronic itch.
Related Products: Bombesin-SAP (Cat. #IT-40), SSP-SAP (Cat. #IT-11), Blank-SAP (Cat. #IT-21)
Featured Article: SP-SAP human clinical trial for cancer pain – an anesthesiologist’s point of view
Noe C, McDermott E (2015) Featured Article: SP-SAP human clinical trial for cancer pain – an anesthesiologist’s point of view. Targeting Trends 16(3)
Related Products: SP-SAP (Cat. #IT-07)
Different immune cells mediate mechanical pain hypersensitivity in male and female mice.
Sorge R, Mapplebeck J, Rosen S, Beggs S, Taves S, Alexander J, Martin L, Austin J, Sotocinal S, Chen D, Yang M, Shi X, Huang H, Pillon N, Bilan P, Tu Y, Klip A, Ji R, Zhang J, Salter M, Mogil J (2015) Different immune cells mediate mechanical pain hypersensitivity in male and female mice. Nat Neurosci 18:1081-1083. doi: 10.1038/nn.4053
Summary: A large and rapidly increasing body of evidence indicates that microglia-to-neuron signaling is essential for chronic pain hypersensitivity. Using multiple approaches, the authors found that microglia are not required for mechanical pain hypersensitivity in female mice; female mice achieved similar levels of pain hypersensitivity using adaptive immune cells, likely T lymphocytes. This sexual dimorphism suggests that male mice cannot be used as proxies for females in pain research. Mac-1-SAP mouse/human toxin (Cat. #IT-06, 15 μg in 8.8 μl) and Saporin control (Cat. #PR-01, 8.8 μg in 8.8 μl) were administered via i.t. injection. The topic of immune system involvement in chronic pain pathophysiology is one of the most active in the pain field; that this sex difference has not been observed until now is very surprising indeed. An important implication of the current findings is that distinct strategies targeting neuroimmune signaling might be required for the treatment of chronic pain in men versus women.
Related Products: Mac-1-SAP mouse/human (Cat. #IT-06), Saporin (Cat. #PR-01)