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Female-specific mechanisms of nociplastic pain in murine model
Hankerd K (2021) Female-specific mechanisms of nociplastic pain in murine model. The University of Texas Medical Branch at Galveston, Dept Neuroscience Thesis.
Objective: To study nociplastic pain the authors developed a murine model in which postinjury thermal stimulation of injured area triggers the transition to a nociplastic pain state more readily in females.
Summary: Postinjury stimulation of an injured area triggers the transition from transient pain to nociplastic pain, females are more susceptible to this transition, and allyl isothiocyanate -sensitive afferents at the previously injured area maintain the nociplastic pain state in a female gonadal hormone-dependent manner.
Usage: Intrathecal injection of Mac-1-SAP (IT-06) 8.85 mM in mice.
Related Products: Mac-1-SAP mouse/human (Cat. #IT-06)
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)
A brief history of saporin and its contributions to neuroscience
Shramm PA, Ancheta LR, Bouajram R, Lappi DA (2021) A brief history of saporin and its contributions to neuroscience. Neuroscience 2021 Abstracts J002.11. Society for Neuroscience, Virtual.
Summary: When investigating the origins of targeted toxins (a drug, therapy, or scientific tool directed to a unique extracellular target), an appropriate place to begin is with the Nobel Prize-winning work of Paul Ehrlich and his concept of the “magic bullet.” Over 100 years later, the use of targeted toxins to perform molecular neurosurgery has become a vital practice that allows researchers to observe changes in organisms after eliminating a neuronal population. A prime example of this practice is the specific targeting of cholinergic neurons in the basal forebrain to mimic Alzheimer’s disease (AD). The research tool designed for this purpose is 192-IgG-Saporin, an antibody conjugated to the ribosome-inactivating protein (RIP) Saporin. Researchers have used this targeted toxin for over 30 years. A 2019 publication by Verkhratsky et al. reviews AD models and states this is the only lesion model that specifically targets cholinergic neurons. In 1983, during a quest to find the optimal payload for a targeted toxin, Fiorenzo Stirpe and colleagues discovered Saporin, a plant protein isolated from the common soapwort plant Saponaria officinalis. Unlike ricin and abrin, Saporin does not have a binding chain and cannot enter a cell on its own. Scientists have devised new ways to use Saporin to advance their research and drug development activities. Just a few examples include: 1. A novel suicide gene therapy approach that uses a vector encoding a double-stranded DNA aptamer to deliver the gene encoding Saporin, 2. Delivery of Saporin encapsulated in a nanotechnology system for development of cancer treatments, 3. A deeper understanding of the difference between pain and itch and the relevant pathways, and 4. Development of a stable epilepsy animal model that is used for screening specific treatments that will lead to micro-methods to eliminate the disease. This review will focus on Saporin as the payload delivered to cells. Targeted toxins (typically targeted by an antibody or peptide chemically linked or genetically fused) provide robust tools for neuroscience where ablation of specific neuronal populations is used to study behavior and function. Saporin is an ideal molecule because of its extreme resistance to high temperatures and denaturation, retention of catalytic activity after conjugation, and lack of a binding chain to allow entrance to the cytoplasm of cells on its own. As a result, it is one of the most studied RIPs used for its vigorousness, potency, safety, and ease of use in the laboratory. The information presented will shed light on the history of Saporin, current applications, and what the future holds for this protein in the neuroscience field.
Related Products: Saporin (Cat. #PR-01)
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.
TRP channels in cancer pain
de Almeida AS, Bernardes LB, Trevisan G (2021) TRP channels in cancer pain. Eur J Pharmacol 904:174185. doi: 10.1016/j.ejphar.2021.174185 PMID: 34015320
Objective: To describe the role of TRP vanilloid 1 (TRPV1) and TRP ankyrin 1 (TRPA1) involved in cancer pain mechanisms.
Summary: Several studies have revealed that the administration of TRPV1 or TRPA1 agonists/antagonists and TRPV1 or TRPA1 knockdown reduced sensitivity to nociception in cancer pain models. Thus, TRP channels are potential targets for managing cancer-related pain syndromes.
Usage: Ablation of IB4 (+) neurons.
Related Products: IB4-SAP (Cat. #IT-10)
See Also:
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)
Activation of spinal dorsal horn astrocytes by noxious stimuli involves descending noradrenergic signaling
Kawanabe R, Yoshihara K, Hatada I, Tsuda M (2021) Activation of spinal dorsal horn astrocytes by noxious stimuli involves descending noradrenergic signaling. Mol Brain 14(1):79. doi: 10.1186/s13041-021-00788-5
Summary: Astrocytes are critical regulators of neuronal function in the central nervous system (CNS). Astrocytes in the spinal dorsal horn (SDH) increase intracellular Ca2+ levels following intraplantar injection of the noxious irritant, formalin, however the underlying mechanisms remain unknown. The authors investigated these mechanisms by focusing on the role of descending noradrenergic (NAergic). Activation of α1A-adrenaline receptors via descending LC-NAergic signals may be a common mechanism underlying astrocytic Ca2+ responses in the SDH evoked by noxious stimuli, including chemical irritants
Usage: Intrathecal treatment with Anti-DBH-SAP, which kills SDH-projecting NAergic neurons, attenuates formalin pain (5.0 µg/20 µl; Martin et al., 1999)
Related Products: Anti-DBH-SAP (Cat. #IT-03)
Developments in understanding diffuse noxious inhibitory controls: pharmacological evidence from pre-clinical research
Kucharczyk MW, Valiente D, Bannister K (2021) Developments in understanding diffuse noxious inhibitory controls: pharmacological evidence from pre-clinical research. J Pain Res 14:1083-1095. doi: 10.2147/JPR.S258602
Summary: This review discusses the pharmacological manipulation interrogation strategies that have been used to examine the functionality of diffuse noxious inhibitory controls (DNIC) and descending control of nociception (DCN).
Usage: Anti-DBH-SAP is one of the drugs tested to influence DNIC expression. They reference a publication that reported that icv injection of Anti-DBH-SAP abolished DCN expression. Anti-DBH-SAP (5 μg/5 μl) was injected in the left ventricle. Lesion of the LC resulted in failure of DNIC, an effect that mimics what is observed behaviorally after chronic TBI.
Related Products: Anti-DBH-SAP (Cat. #IT-03)