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Neuraxial drug delivery in pain management: An overview of past, present, and future
Yaksh TL, dos Santo G, Lemes J, Malange K (2023) Neuraxial drug delivery in pain management: An overview of past, present, and future. Anaesthesiology doi: 10.1016/j.bpa.2023.04.003
Objective: Activation of neuraxial nociceptive linkages leads to a high level of encoding of the message that is transmitted to the brain and that can initiate a pain state with its attendant emotive covariates. The authors review the encoding of this message and describe the how it is subject to regulation by pharmacological targeting of dorsal root ganglion and dorsal horn systems.
Summary: Authors provide an overview of the past, present and future directions of the biology, pharmacology and technology relevant to the use of the neuraxial route. SP-SAP was used as a neuraxial toxin to eliminate NK1R expressing cells, which characteristic of neurons known to be the second order neurons responding to C fiber input. Delivery of SP-SAP results in long-lasting loss of NK1 bearing dorsal horn neurons and analgesia.
Related Products: SP-SAP (Cat. #IT-07)
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)
Adrenergic signalling to astrocytes in anterior cingulate cortex contributes to pain-related aversive memory in rats
Iqbal Z, Lei Z, Ramkrishnan AS, Liu S, Hasan M, Akter M, Lam YY, Li Y (2023) Adrenergic signalling to astrocytes in anterior cingulate cortex contributes to pain-related aversive memory in rats. Commun Biol 6:10. doi: 10.1038/s42003-022-04405-6 PMID: 36604595
Objective: To identify the role of norepinephrine in colorectal distention (sub-threshold for acute pain) induced conditioned place avoidance and plasticity gene expression in the anterior cingulate cortex (ACC).
Summary: The findings suggest that projection-specific adrenergic astrocytic signaling in ACC is integral to system-wide neuromodulation in response to visceral stimuli and plays a key role in mediating pain-related aversion consolidation and memory formation.
Usage: 0.25 ug of Anti-DBH-SAP (1 μg/μl) was injected into each hemisphere of locus coeruleus (LC).
Related Products: Anti-DBH-SAP (Cat. #IT-03)
Prenatal exposure to valproic acid causes allodynia associated with spinal microglial activation
Imado E, Sun S, Abawa AR, Tahara T, Kochi T, Huynh TNB, Asano S, Hasebe S, Nakamura Y, Hisaoka-Nakashima K, Kotake Y, Irifune M, Tsuga K, Takuma K, Morioka N, Kiguchi N, Ago Y (2022) Prenatal exposure to valproic acid causes allodynia associated with spinal microglial activation. Neurochem Int 160:105415. doi: 10.1016/j.neuint.2022.105415
Objective: To further understand the mechanism underlying sensory phenotypes in autism spectrum disorder (ASD).
Summary: The authors investigated the age-dependent tactile sensitivity in an animal model of ASD induced by prenatal exposure to valproic acid and subsequently assessed the involvement of microglia in the spinal cord in pain processing.
Usage: To deplete microglia in the spinal cord, Mac-1-SAP (11.2 μg/5.5 μl) was injected intrathecally at the level of L4–L5 in adult (8-week-old) mice.
Related Products: Mac-1-SAP mouse/human (Cat. #IT-06)
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)
Noradrenergic innervations of the medial prefrontal cortex mediate empathy for pain in rats via the α1 and β receptors.
Yun-Fei L, Zhang J, Wang XQ, Peng JJ, Ling BF, Liu FT, Yang F, Dong G, Yu YQ (2022) Noradrenergic innervations of the medial prefrontal cortex mediate empathy for pain in rats via the α1 and β receptors. Behav Brain Res 10:113828. doi: 10.1016/j.bbr.2022.113828
Objective: To study the roles of the locus coeruleus (LC) to medial prefrontal cortex (mPFC) pathway in pain empathy in rats.
Summary: Results indicate that noradrenergic innervations in the mPFC mediate empathy for pain in rats via the α1 and β receptors.
Usage: Noradrenergic innervations of the mPFC were selectively eliminated through intra-mPFC injections of Anti-DBH-SAP.
Related Products: Anti-DBH-SAP (Cat. #IT-03)
Maintenance mechanism of nociplastic pain in males
McDonough KE (2022) Maintenance mechanism of nociplastic pain in males. University of Texas Medical Branch Thesis.
Objective: The objective of this dissertation is to elucidate the sex-specific mechanisms underlying the transition to and maintenance of a nociplastic pain state using animal models.
Summary: This PhD dissertation investigates the mechanisms underlying the transition from acute to chronic nociplastic pain using murine models. The study finds that in males, spinal microglial activation driven by GABAergic disinhibition allows normally innocuous stimulation to induce a transition to nociplastic pain maintained by spinal microglia and proinflammatory cytokines.
Usage: Intrathecal injection of Saporin or Mac-1-SAP at 8.85 μM.
Related Products: Mac-1-SAP mouse/human (Cat. #IT-06), Saporin (Cat. #PR-01)
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)