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Locus coeruleus-noradrenergic modulation of trigeminal pain: Implications for trigeminal neuralgia and psychiatric comorbidities
Donertas-Ayaz B, Caudle RM (2023) Locus coeruleus-noradrenergic modulation of trigeminal pain: Implications for trigeminal neuralgia and psychiatric comorbidities. Neurobiol Pain 13:100124. doi: 10.1016/j.ynpai.2023.100124 PMID: 36974102
Objective: To summarize the knowledge about the involvement of noradrenaline in acute and chronic trigeminal pain conditions and how the activity of the locus coeruleus (LC) noradrenergic neurons changes in response to acute and chronic pain conditions and how these changes might be involved in pain-related comorbidities including anxiety, depression, and sleep disturbance.
Summary: LC inhibition of nociceptive transmission in acute pain and in longterm neuropathic pain increases the tonic activity of LC-NA neurons. These changes may contribute to impaired descending pain modulation and pain-related comorbidities such as depression, anxiety, and sleep disorders.
Usage: Elimination of NA neurons via injection of anti-dopamine β-hydroxylase-saporin (Anti-DBH-SAP) into the lateral ventricle and trigeminal brainstem nuclei three weeks after infraorbital nerve injury attenuated mechanical allodynia
Related Products: Anti-DBH-SAP (Cat. #IT-03)
Featured Article: Selective ablation of IB4+ primary afferent neurons reduces mechanical and cold hyperalgesia in an EAE mouse model of multiple sclerosis
Nguyen KL, Lamerand SR, Deshpande RP, Taylor BK (2021) Featured Article: Selective ablation of IB4+ primary afferent neurons reduces mechanical and cold hyperalgesia in an EAE mouse model of multiple sclerosis. Targeting Trends 22
Related Products: IB4-SAP (Cat. #IT-10), Blank-SAP (Cat. #IT-21)
Read the featured article in Targeting Trends.
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A spinal microglia population involved in remitting and relapsing neuropathic pain
Kohno K, Shirasaka R, Yoshihara K, Mikuriya S, Tanaka K, Takanami K, Inoue K, Sakamoto H, Ohkawa Y, Masuda T, Tsuda M (2022) A spinal microglia population involved in remitting and relapsing neuropathic pain. Science 376(6588):86-90. doi: 10.1126/science.abf6805
Objective: To investigate pain recovery mechanisms.
Summary: The authors reveal a mechanism for the remission and recurrence ofneuropathic pain, providing potential targets for therapeutic strategies.
Usage: The dose of CTB-SAP and IB4-SAP was 8 ug/10 uL, diluted in PBS.
Related Products: CTB-SAP (Cat. #IT-14), IB4-SAP (Cat. #IT-10)
Contribution of small diameter non-peptidergic primary afferent neurons to central neuropathic pain in a new, more clinically relevant mouse model of multiple sclerosis
Nguyen KL, Lamerand SR, Deshpande RP, Taylor BK (2021) Contribution of small diameter non-peptidergic primary afferent neurons to central neuropathic pain in a new, more clinically relevant mouse model of multiple sclerosis. Neuroscience 2021 Abstracts P377/07. Society for Neuroscience, Virtual.
Summary: Over 50% of multiple sclerosis (MS) patients suffer from neuropathic pain (MSNP). Current treatments give inadequate relief due to incomplete understanding of underlying mechanisms. Recent electrophysiological recordings of primary afferent neurons (PAN) in the dorsal root ganglion (DRG) following experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, revealed increased afterhyperpolarization in small-diameter fibers. These data form the premise of our goal to understand the contribution of small-diameter (peptidergic or non-peptidergic) PANs to MSNP. Arguably the most common method to induce EAE is administration of myelin oligodendrocyte glycoprotein (MOG) to generate an autoimmune response targeting the myelin sheath. A MOG fragment is typically given with two adjuvants: complete Freund’s adjuvant (CFA) to boost immunogenicity and pertussis toxin (PTX) to breakdown the blood-brain barrier and facilitate CNS immune cell infiltration. However, PTX can disrupt G-protein coupled receptors, cause pain, and alter autoimmune response gene expression. In 10-week-old C57BL/6 mice, we conducted the first rigorous comparison of a classic PTX EAE model with the novel non-PTX (nPTX) EAE model. We found that both PTX and nPTX EAE mouse models showed the same degree of: 1) motor deficits; 2) plantar hindpaw mechanical and cold hypersensitivity (except cold hypersensitivity resolved more quickly after PTX EAE than nPTX EAE); and 3) lumbar spinal cord demyelination. Unlike most rodent models of MS including PTX EAE, the nPTX EAE group exhibited somatosensory cortex demyelination, a core feature of MS in human patients and cold hypersensitivity. We suggest nPTX EAE to be the most clinically relevant rodent model available to study not only MSNP, but MS in general. To evaluate the contribution of peptidergic and non-peptidergic neurons to MSNP, we induced nPTX EAE. After 12 days we administered capsaicin (10µg/mouse, i.t.) or IB4-saporin (1.5µg/mouse, i.t.) to primarily ablate peptidergic or nonpeptidergic C-fibers, respectively. Ablation efficacy was successfully confirmed with dramatic loss in DRG of TRPV1/CGRP immunoreactivity (peptidergic C-fibers) following capsaicin, and IB4 immunoreactivity (nonpeptidergic C-fibers) following IB4-saporin. IB4-saporin, but not capsaicin, partially reduced mechanical hypersensitivity and reversed cold hypersensitivity within 9 days. These data suggest nonpeptidergic but not peptidergic C-fibers contribute to MSNP. Our next studies will use genetic knockout, chemogenetic, and optogenetic strategies using MrgprdCreER mice to modulate the activity of nonpeptidergic C-fibers.
Related Products: IB4-SAP (Cat. #IT-10)
Role of microglia and astrocytes in spinal cord injury induced neuropathic pain
Miranpuri GS, Bali P, Nguyen J, Kim JJ, Modgil S, Mehra P, Buttar S, Brown G, Yutuc N, Singh H, Wood A, Singh J, Anand A (2021) Role of microglia and astrocytes in spinal cord injury induced neuropathic pain. Ann Neurosci 28(3-4):219-228. doi: 10.1177/09727531211046367
Summary: Given the severity and incapacitating effects of spinal cord injury neuropathic pain (SCINP), it is imperative to study the pathways involved and find new therapeutic targets in coordination with stem cell research, and to develop a new gold-standard in SCINP treatment. Chronic inflammation by microglia, when targeted with Mac-1-SAP, helps in pain reversal.
Related Products: Mac-1-SAP rat (Cat. #IT-33)
Pain and depression comorbidity causes asymmetric plasticity in the locus coeruleus neurons
Llorca-Torralba M, Camarena-Delgado C, Suárez-Pereira I, Bravo L, Mariscal P, Garcia-Partida JA, López-Martín C, Wei H, Pertovaara A, Mico JA, Berrocoso E (2022) Pain and depression comorbidity causes asymmetric plasticity in the locus coeruleus neurons. Brain 145(1):154-167. doi: 10.1093/brain/awab239
Summary: There is strong comorbidity between chronic pain and depression. This study explores how this comorbidity occurs. The authors refer to published research that shows icv administration of anti-DBH-SAP or intra-LC administration of lidocaine dampened the evoked pain in conditions of long-term nerve-injury. However, icv injection of anti-DBH-SAP disrupts all noradrenergic nuclei (A1-A7), some of which contribute to sensorial hypersensitivity.
Related Products: Anti-DBH-SAP (Cat. #IT-03)
See Also:
- Brightwell JJ et al. Noradrenergic Neurons in the Locus Coeruleus Contribute to Neuropathic Pain. Neuroscience 160:174-185, 2009.
- Marques-Lopes J et al. The hyperalgesic effects induced by the injection of angiotensin II into the caudal ventrolateral medulla are mediated by the pontine A(5) noradrenergic cell group. Brain Res 1325:41-52, 2010.
Studying human nociceptors: from fundamentals to clinic
Middleton SJ, Barry AM, Comini M, Li Y, Ray PR, Shiers S, Themistocleous AC, Uhelski ML, Yang X, Dougherty PM, Price TJ, Bennett DL (2021) Studying human nociceptors: from fundamentals to clinic. Brain 144(5):1312-1335. doi: 10.1093/brain/awab048
Summary: The authors injected 5 µg of IB4-SAP into the sciatic nerve in the left thigh. Lesioned animals displayed attenuated NGF-induced hyperalgesia, as well as differences in other pain-model markers.
Related Products: IB4-SAP (Cat. #IT-10)
Antiplexin D1 antibodies relate to small fiber neuropathy and induce neuropathic pain in animals
Fujii T, Lee EJ, Miyachi Y, Yamasaki R, Lim YM, Iinuma K, Sakoda A, Kim KK, Kira JI (2021) Antiplexin D1 antibodies relate to small fiber neuropathy and induce neuropathic pain in animals. Neurol Neuroimmunol Neuroinflamm 8(5):e1028. doi: 10.1212/NXI.0000000000001028
Summary: NeP patient-derived plexin D1-IgG selectively binds to isolectin B4-positive unmyelinated C-fiber type small DRG neurons that sense mechanical pain.
Related Products: IB4-SAP (Cat. #IT-10)
CSF-CN contributes to cancer-induced bone pain via the MKP-1-mediated MAPK pathway
Chen P, Pan M, Lin QS, Lin XZ, Lin Z (2021) CSF-CN contributes to cancer-induced bone pain via the MKP-1-mediated MAPK pathway. Biochem Biophys Res Commun 547:36-43. doi: 10.1016/j.bbrc.2021.02.010
Summary: Cerebrospinal fluid-contacting nucleus (CSF–CN) has been reported to be involved in the development of neuropathic pain and inflammatory pain. This study aimed to see whether it also has a role in cancer-induced bone pain (CIBP). Targeted ablation of CSF-CN dramatically aggravated pain sensitivity.
Usage: Injection via icv of CTB-SAP was performed to “knockout” the CSF-CN.
Related Products: CTB-SAP (Cat. #IT-14)
Targeting spinal neuropeptide Y1 receptor-expressing interneurons to alleviate chronic pain and itch
Nelson TS, Taylor BK (2021) Targeting spinal neuropeptide Y1 receptor-expressing interneurons to alleviate chronic pain and itch. Prog Neurobiol 196:101894. doi: 10.1016/j.pneurobio.2020.101894
Summary: Intrathecal administration of NPY-SAP reduced several operant and cognitive measures of Complete Freund’s adjuvant (CFA)-induced allodynia, including responsiveness to cold temperatures, feeding interference, and an escape task, but did not interfere with systemic morphine-induced analgesia. (Wiley et al.) Similar to the spared nerve injury (SNI) model of neuropathic pain, NPY-SAP dose-dependently reduced the development of mechanical allodynia (hindpaw withdrawal response to von Frey filaments), mechanical hyperalgesia (response to blunt pin), and cold allodynia (hindpaw withdrawal response duration to acetone droplet evaporation). (Nelson et al.) Together, these directed lesion studies support the idea that the Y1-IN subpopulation of dorsal horn neurons is necessary for the maintenance of both mechanical and cold modalities of nociceptive transmission in chronic pain states.
Related Products: NPY-SAP (Cat. #IT-28)
See Also:
- Wiley RG et al. Neuropeptide Y receptor-expressing dorsal horn neurons: role in nocifensive reflex responses to heat and formalin. Neuroscience 161:139-147, 2009.
- Nelson TS et al. Facilitation of neuropathic pain by the NPY Y1 receptor-expressing subpopulation of excitatory interneurons in the dorsal horn. Sci Rep 9(1):7248, 2019.