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[Targeted damage of the cerebrospinal fluid-contacting nucleus contributes to the pain behavior and the expression of 5-HT and c-Fos in spinal dorsal horn of rats].
Cao J, Wu T, Zhang L (2014) [Targeted damage of the cerebrospinal fluid-contacting nucleus contributes to the pain behavior and the expression of 5-HT and c-Fos in spinal dorsal horn of rats]. Zhongguo Ying Yong Sheng Li Xue Za Zhi 30:218-222.
Summary: Pain threshold, 5-hydroxytryptamine (5-HT) expression, and c-Fos expression were measured in rats after treatment with CTB-SAP (Cat. #IT-14). Use of CTB-SAP reduced the number of neurons in the cerebrospinal fluid (CSF)-contacting nucleus over time until no neurons could be detected by the 10th day post-injection. 5-HT and c-Fos expression in the spinal dorsal horn gradually increased, and was negatively correlated with the pain threshold. The data indicate that neurons in the CSF-contacting nucleus are involved in pain regulation, and that expression of 5-HT and c-Fos is part of this regulatory pathway.
Related Products: CTB-SAP (Cat. #IT-14)
Role for monocyte chemoattractant protein-1 in the induction of chronic muscle pain in the rat.
Alvarez P, Green P, Levine J (2014) Role for monocyte chemoattractant protein-1 in the induction of chronic muscle pain in the rat. Pain 155:1161-1167. doi: 10.1016/j.pain.2014.03.004
Summary: In order to better understand where monocyte chemoattractant protein 1 (MCP-1) fits in the chronic pain landscape the authors performed a series of experiments using antisense and mismatch oligodeoxynucleotides against the MCP-1 receptor in rats. Some animals also received 3.2 μg intrathecal injections of IB4-SAP (Cat. #IT-10). IB4-SAP treatment removed water avoidance stress-induced muscle hyperalgesia, as well as preventing stress-induced hyperalgesic priming that is a usual response to administration of MCP-1. The data indicate that MCP-1 takes action through its receptors on IB4+ nociceptors.
Related Products: IB4-SAP (Cat. #IT-10)
TrkA in vivo function is negatively regulated by ubiquitination.
Kiris E, Wang T, Yanpallewar S, Dorsey S, Becker J, Bavari S, Palko M, Coppola V, Tessarollo L (2014) TrkA in vivo function is negatively regulated by ubiquitination. J Neurosci 34:4090-4098. doi: 10.1523/JNEUROSCI.4294-13.2014 PMID: 24623787
Summary: The high affinity nerve growth factor receptor, trkA, plays an intrinsic role in the regulation of various aspects of the mammalian nervous system. The post-translational attachment of ubiquitin to trkA plays a role in the final disposition and function of many proteins; in this work the authors investigate the result of trkA ubiquitination. By removing a 3 amino acid sequence from the receptor the ubiquitination of TrkA was reduced which resulted in an increase in TrkA protein levels and activity. In mice containing this mutation, the rise in TrkA activity was accompanied by enhanced thermal sensitivity and inflammatory pain. Anti-trkA (Cat. #AB-N03) was used at a concentration of 1:500 in immunohistochemistry.
Related Products: trkA Rabbit Polyclonal (Cat. #AB-N03)
IB4(+) and TRPV1(+) sensory neurons mediate pain but not proliferation in a mouse model of squamous cell carcinoma.
Ye Y, Bae S, Viet CT, Troob S, Bernabe D, Schmidt BL (2014) IB4(+) and TRPV1(+) sensory neurons mediate pain but not proliferation in a mouse model of squamous cell carcinoma. Behav Brain Funct 10(1):5. doi: 10.1186/1744-9081-10-5
Objective: To evaluate subtypes of sensory neurons involved in cancer pain and proliferation.
Summary: IB4(+) neurons play an important role in cancer-induced mechanical allodynia, while TRPV1 mediates cancer-induced thermal hyperalgesia. Characterization of the sensory fiber subtypes responsible for cancer pain could lead to the development of targeted therapeutics.
Usage: IB4(+) neurons play an important role in cancer-induced mechanical allodynia, while TRPV1 mediates cancer-induced thermal hyperalgesia. Characterization of the sensory fiber subtypes responsible for cancer pain could lead to the development of targeted therapeutics.
Related Products: IB4-SAP (Cat. #IT-10), Saporin (Cat. #PR-01)
Gabapentin increases extracellular glutamatergic level in the locus coeruleus via astroglial glutamate transporter-dependent mechanisms.
Suto T, Severino AL, Eisenach JC, Hayashida KI (2014) Gabapentin increases extracellular glutamatergic level in the locus coeruleus via astroglial glutamate transporter-dependent mechanisms. Neuropharmacology 81C:95-100. doi: 10.1016/j.neuropharm.2014.01.040
Summary: Gabapentin is effective in reducing acute and chronic pain, but the mechanisms by which it works are not well understood. The authors assessed extracellular glutamate levels and glutamate interaction with several different cellular membrane proteins. Rats received a 0.25 μg injection of anti-DBH-SAP (Cat. #IT-03) into the locus coeruleus (LC) in order to deplete noradreline levels. Mouse IgG-SAP (Cat. #IT-18) was used as a control. The gabapentin-induced glutamate increase in the LC was not affected by the lesion, supporting data indicating that gabapentin induces glutamate release from astrocytes to stimulate descending inhibition.
Related Products: Anti-DBH-SAP (Cat. #IT-03), Mouse IgG-SAP (Cat. #IT-18)
Ablating spinal NK1-bearing neurons eliminates the development of pain and reduces spinal neuronal hyperexcitability and inflammation from mechanical joint injury in the rat.
Weisshaar CL, Winkelstein BA (2014) Ablating spinal NK1-bearing neurons eliminates the development of pain and reduces spinal neuronal hyperexcitability and inflammation from mechanical joint injury in the rat. J Pain 15(4):378-386. doi: 10.1016/j.jpain.2013.12.003
Summary: A high percentage of chronic neck pain involves the facet joint. Although the facet joint is innvervated by peptide-responsive nociceptive afferents, the role of these cells in the development and modulation of nociceptive signaling remains unclear. Using a previously developed rat model of facet joint injury, the authors examined the role of neurokinin-1 receptor-expressing spinal cells in this pathway. Rats received 100 ng SSP-SAP (Cat. #IT-11) via lumbar puncture. Blank-SAP (Cat. #IT-21) was used as a control. The results demonstrate that spinal NK1r-expressing cells are essential for nociception and inflammation due to a mechanical joint injury.
Related Products: SSP-SAP (Cat. #IT-11), Blank-SAP (Cat. #IT-21)
Male and female mice use distinct spinal immune cells to mediate chronic pain.
Sorge RE, Martin LJ, Alexander J, Beggs S, Rosen S, Zhang J, Salter MW, Mogil JS (2013) Male and female mice use distinct spinal immune cells to mediate chronic pain. Neuroscience 2013 Abstracts 642.11. Society for Neuroscience, San Diego, CA.
Summary: There are clear sex differences in the sensitivity to painful stimuli and analgesics in humans and animals. Some data suggest that pain processing is mediated by separable pathways in male and female mice, for example we recently demonstrated that spinal cord toll-like receptor 4 is used to mediate chronic pain in male, but not female mice. Here, we sought to investigate the sex-dependent pathways involved in spinal mediation of pain in male and female mice. First, we found that allodynia induced by complete Freund’s adjuvant (CFA) or spared nerve injury (SNI) was reversible via intrathecal glial inhibitors (minocycline, 0-300 μg; fluorocitrate, 0-1.5 nmol; propentofylline, 0-75 μg), or glial cell depletion using Mac1-saporin, only in male mice and never in intact female mice. This suggests that female mice utilize a microglia-independent spinal pathway to mediate chronic pain. To investigate whether T cells might mediate chronic pain in female mice, we used two strains of T cell-deficient animals; Rag1 (Rag1tm1Mom) and nude CD1 (Crl: CD1-Foxn1nu). In both strains, SNI- or CFA-induced allodynia was reversible in female mice by glial inhibitors, similar to male mice. This effect was prevented through adoptive transfer of wild type (C57BL/6) splenocytes to Rag1 female mice, suggesting T-cell involvement. T-cell infiltration into the CNS was reduced with an antibody to β1-integrin; this manipulation transiently reversed allodynia in female mice, but not male mice, further confirming that T cells mediate chronic pain in females. Finally, castration was found to reduce the anti-allodynic effect of glial inhibitors and enhanced the potential of anti-β1 integrin in male mice. In contrast, ovariectomy with testosterone replacement in female mice eliminated the effect of anti-β1 integrin and enhanced the effect of glial inhibitors. We have uncovered a robust, qualitative, and previously unknown sex difference in spinal mediation of chronic pain in mice. Attention to this critical sex difference in pain mediation may be vital to future pharmaceutical development and to interpretation of clinical pain treatments that focus on one system or the other in a mixed-sex population.
Related Products: Mac-1-SAP mouse/human (Cat. #IT-06)
Descending noradrenergic control of conditioned pain modulation and postoperative pain trajectory in rats.
Parker RA, Wang F, Hayashida K, Martin TJ, Eisenach JC, Peters CM (2013) Descending noradrenergic control of conditioned pain modulation and postoperative pain trajectory in rats. Neuroscience 2013 Abstracts 461.10. Society for Neuroscience, San Diego, CA.
Summary: Aim of Investigation: Chronic pain after surgery (CPAS) is now recognized as a significant clinical problem that occurs in 10-50% of patients undergoing surgery. Recent clinical studies demonstrate the integrity of endogenous pain inhibitory controls are important for preventing CPAS, however this relationship and underlying mechanisms haven’t been examined in preclinical models. We hypothesized that a causal relationship exists between impaired endogenous analgesia and chronic pain after surgery that is in part dependent on descending noradrenergic pathways. Methods: We examined the integrity of endogenous analgesia in rats preoperatively used a previously described method for assessing conditioned pain modulation (CPM) in rats (Ferrari et al., 2010) involving injection of capsaicin (150μg/50μl) in the forepaw as a conditioning stimulus and detection of hindpaw mechanical thresholds (Randall-Selitto device) as the test stimulus. The partial L5 spinal nerve ligation (pSNL) model and mixed effects growth curve modeling of mechanical withdrawal thresholds assessed for 10 weeks following surgery were used to study resolution of postoperative mechanical hypersensitivity. The role of descending spinal noradrenergic pathways in CPM and postoperative trajectory was assessed by ablating spinal noradrenergic fibers with DβH-saporin or blocking their activity pharmacologically with adrenergic receptor antagonists. Results: Forepaw capsaicin resulted in release of NE in the lumbar spinal cord and this CPM paradigm was partially prevented by spinal idazoxan (30μg, i.t.). CPM assessed preoperatively resulted in pronounced but variable increases in hindpaw mechanical withdrawal thresholds at 30 minutes (range: 60-140g). Within individual rats, we observed a significant correlation between the degree of preoperative CPM and the slope of trajectory (P=0.006, r=0.610) as rats with lower endogenous analgesia had slower resolution of mechanical hypersensitivity. In support of a causal role between endogenous spinal noradrenergic activity and CPAS, depletion of spinal noradrenergic fibers prior to pSNL resulted in a significant reduction in the slope of trajectory within the ipsilateral hindpaw. Conclusions: Collectively, these studies suggest that the ability to engage descending endogenous noradrenergic pathways may be critical in determining whether CPAS develops. Furthermore, the use of growth curve modeling to study CPAS will allow us to examine the ability of socio-environmental conditions or pharmacological interventions to impair or improve aspects of postoperative pain trajectory as part of future studies.
Related Products: Anti-DBH-SAP (Cat. #IT-03)
Neuroprotection with gonadal steroids following partial motoneuron depletion: Dependence on steroid receptor activation and hormone action at the target musculature.
Sengelaub DR, Cai Y, Chung M, Mnayarji (2013) Neuroprotection with gonadal steroids following partial motoneuron depletion: Dependence on steroid receptor activation and hormone action at the target musculature. Neuroscience 2013 Abstracts 467.12. Society for Neuroscience, San Diego, CA.
Summary: Aim of Investigation: Chronic pain after surgery (CPAS) is now recognized as a significant clinical problem that occurs in 10-50% of patients undergoing surgery. Recent clinical studies demonstrate the integrity of endogenous pain inhibitory controls are important for preventing CPAS, however this relationship and underlying mechanisms haven’t been examined in preclinical models. We hypothesized that a causal relationship exists between impaired endogenous analgesia and chronic pain after surgery that is in part dependent on descending noradrenergic pathways. Methods: We examined the integrity of endogenous analgesia in rats preoperatively used a previously described method for assessing conditioned pain modulation (CPM) in rats (Ferrari et al., 2010) involving injection of capsaicin (150μg/50μl) in the forepaw as a conditioning stimulus and detection of hindpaw mechanical thresholds (Randall-Selitto device) as the test stimulus. The partial L5 spinal nerve ligation (pSNL) model and mixed effects growth curve modeling of mechanical withdrawal thresholds assessed for 10 weeks following surgery were used to study resolution of postoperative mechanical hypersensitivity. The role of descending spinal noradrenergic pathways in CPM and postoperative trajectory was assessed by ablating spinal noradrenergic fibers with DβH-saporin or blocking their activity pharmacologically with adrenergic receptor antagonists. Results: Forepaw capsaicin resulted in release of NE in the lumbar spinal cord and this CPM paradigm was partially prevented by spinal idazoxan (30μg, i.t.). CPM assessed preoperatively resulted in pronounced but variable increases in hindpaw mechanical withdrawal thresholds at 30 minutes (range: 60-140g). Within individual rats, we observed a significant correlation between the degree of preoperative CPM and the slope of trajectory (P=0.006, r=0.610) as rats with lower endogenous analgesia had slower resolution of mechanical hypersensitivity. In support of a causal role between endogenous spinal noradrenergic activity and CPAS, depletion of spinal noradrenergic fibers prior to pSNL resulted in a significant reduction in the slope of trajectory within the ipsilateral hindpaw. Conclusions: Collectively, these studies suggest that the ability to engage descending endogenous noradrenergic pathways may be critical in determining whether CPAS develops. Furthermore, the use of growth curve modeling to study CPAS will allow us to examine the ability of socio-environmental conditions or pharmacological interventions to impair or improve aspects of postoperative pain trajectory as part of future studies.
Related Products: Anti-DBH-SAP (Cat. #IT-03)
Role of nonpeptidergic subset of primary afferent neurons in inflammatory hypernociception in mice.
Pinto LG, Souza GR, Lopes AHP, Talbot J, Cunha FQ, Cunha TM, Ferreira SH (2013) Role of nonpeptidergic subset of primary afferent neurons in inflammatory hypernociception in mice. Neuroscience 2013 Abstracts 256.15. Society for Neuroscience, San Diego, CA.
Summary: Sensory information is transmitted from the periphery to the spinal cord by distinct subsets of primary afferent neurons, including small diameter unmyelinated C-fibers, which plays an important role in detecting noxious stimuli. C-fiber nociceptors have been divided into two classes, the peptidergic and nonpeptidergic. While many of the differences between peptidergic and nonpeptidergic neurons are now appreciated, a possible functional difference between these two classes of C fibers in the genesis of acute nociception as well as inflammatory pain is still unclear. Thus, this study aims to clarify the role of nonpeptidergic C fibers in acute nociception induced by mechanical, thermal and chemical stimuli as well as in inflammatory hypernociception. In order to elucidate differences between these two classes of C fibers, a neurotoxin was used to selectively eliminate the nonpeptidergic C fibers: a saporin conjugated to isolectin B4 (IB4). Nociceptive threshold was evaluated through thermal (Hargreaves) and mechanical (filaments and electronic von Frey) tests in C57BL/6 mice. Nociception models were induced by intraplantar (i.pl.) injection of capsaicin and formalin (acute nociception) or by i.pl. administration of prostaglandin E2 (PGE2), epinephrine, endothelin, NGF, GDNF and carrageenan (inflammatory hypernociception). P2X3 and TRPV1 expression were analyzed by Western blot of dorsal root ganglion (DRG). The expression of IB4-labeled in spinal cord was determined by immunofluorescense using confocal microcopy. Firstly, it was observed that the intrathecal administration of IB4-saporin did not change baseline thermal and mechanical nociceptive threshold of the mice paw when compared to saline and saporin-control groups. The intrathecal administration of IB4-saporin reduced mechanical inflammatory hypernociception induced by carrageenan, epinephrine, endothelin, PGE2 or GDNF, but not NGF, in mice. Similarly, the treatment with IB4-saporin inhibited the nociception caused by intraplantar injection of the capsaicin. By contrast, the acute nociception induced by formalin did not change by administration of IB4-saporin. In addition, the expression of TRPV1 and P2X3 in DRG were reduced after treatment with IB4-saporin. Consistent with these findings, we found that IB4-saporin injection decreased the expression of IB4-labeled in spinal cord. These results suggest that absence the nonpeptidergic C fibers does not affect basal nociceptive threshold. However, these fibers are essential for the development of nociception in the paw of mice induced by inflammatory stimuli like PGE2, epinephrine, endothelin, carrageenan and capsaicin.
Related Products: IB4-SAP (Cat. #IT-10)