Anti-nociceptive effect of a conjugate of substance P and light chain of botulinum neurotoxin type A

Mustafa, Golam; Anderson, Ethan M.; Bokrand-Donatelli, Yvonne; Neubert, John K.; Caudle, Robert M.

doi:10.1016/j.pain.2013.07.041

Cited by 48 publications

(28 citation statements)

References 42 publications

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“…The NK1r reduces the behavioral response to pain and the pain-induced c-Fos activation in distinct brain areas which are intimately linked with nociceptive neurotransmission and the initiation and integration of central stress responses [107]. Mustafa et al [108] have demonstrated that SP-BoNT/A LC conjugate can internalize BoNT/A LC selectively to NK1r-expressing neurons and delivers the LC inside the NK1r neurons. Internalized LC cleaves the SNAP-25 and can alleviate nociceptive behavior in a chemotherapy induced neuropathic pain [108].…”

Section: By Blocking the Release Of Neurotransmittersmentioning

confidence: 99%

Therapeutic use of botulinum toxin in pain treatment

Kumar

2018

Neuronal Signaling

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Correspondence: Raj Kumar (rkumar@inads.org)Botulinum toxin is one of the most potent molecule known to mankind. A neurotoxin, with high affinity for cholinergic synapse, is effectively capable of inhibiting the release of acetylcholine. On the other hand, botulinum toxin is therapeutically used for several musculoskeletal disorders. Although most of the therapeutic effect of botulinum toxin is due to temporary skeletal muscle relaxation (mainly due to inhibition of the acetylcholine release), other effects on the nervous system are also investigated. One of the therapeutically investigated areas of the botulinum neurotoxin (BoNT) is the treatment of pain. At present, it is used for several chronic pain diseases, such as myofascial syndrome, headaches, arthritis, and neuropathic pain. Although the effect of botulinum toxin in pain is mainly due to its effect on cholinergic transmission in the somatic and autonomic nervous systems, research suggests that botulinum toxin can also provide benefits related to effects on cholinergic control of cholinergic nociceptive and antinociceptive systems. Furthermore, evidence suggests that botulinum toxin can also affect central nervous system (CNS). In summary, botulinum toxin holds great potential for pain treatments. It may be also useful for the pain treatments where other methods are ineffective with no side effect(s). Further studies will establish the exact analgesic mechanisms, efficacy, and complication of botulinum toxin in chronic pain disorders, and to some extent acute pain disorders.

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Section: By Blocking the Release Of Neurotransmittersmentioning

confidence: 99%

Therapeutic use of botulinum toxin in pain treatment

Kumar

2018

Neuronal Signaling

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“…A large body of evidence suggests that the N terminal of SP can be utilized to generate conjugated molecules without losing the ability of the peptide to bind and activate the NK1 receptor. This strategy has been successfully used for delivery of several different toxins including saporin (Mantyh et al, 1997), diphtheria (Benoliel et al, 1999), cholera (Caudle et al, 2007) and, more recently, botulinum toxin (Mustafa et al, 2013) ]tachykinins were linked together with the PWT2 core using a thio-Michael reaction. As in our results obtained using the N/OFQ sequence, the reaction proceeded in a few minutes and was characterized by an extremely high yield and purity of the final products: PWT2-SP, PWT2-NKA and PWT2-NKB.…”

Section: Bjp C Ruzza Et Almentioning

confidence: 99%

Pharmacological characterization of tachykinin tetrabranched derivatives

Ruzza

Rizzi

Malfacini

et al. 2014

British J Pharmacology

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Keywordstachykinins; substance P; PWT2-SP; NK1 receptor; calcium mobilization; bioluminescence resonance energy transfer; guinea pig ileum; rat urinary bladder; nociceptive behaviour induced by spinal substance P; mice BACKGROUND AND PURPOSEPeptide welding technology (PWT) is a novel chemical strategy that allows the synthesis of multibranched peptides with high yield, purity and reproducibility. Using this technique, we have synthesized and pharmacologically characterized the tetrabranched derivatives of the tachykinins, substance P (SP), neurokinin A (NKA) and B (NKB). EXPERIMENTAL APPROACHThe following in vitro assays were used: calcium mobilization in cells expressing human recombinant NK receptors, BRET studies of G-protein -NK1 receptor interaction, guinea pig ileum and rat urinary bladder bioassays. Nociceptive behavioural response experiments were performed in mice following intrathecal injection of PWT2-SP. KEY RESULTSIn calcium mobilization studies, PWT tachykinin derivatives behaved as full agonists at NK receptors with a selectivity profile similar to that of the natural peptides. NK receptor antagonists display similar potency values when tested against PWT2 derivatives and natural peptides. In BRET and bioassay experiments PWT2-SP mimicked the effects of SP with similar potency, maximal effects and sensitivity to aprepitant. After intrathecal administration in mice, PWT2-SP mimicked the nociceptive effects of SP, but with higher potency and a longer-lasting action. Aprepitant counteracted the effects of PWT2-SP in vivo. CONCLUSIONS AND IMPLICATIONSThe present study has shown that the PWT technology can be successfully applied to the peptide sequence of tachykinins to generate tetrabranched derivatives characterized with a pharmacological profile similar to the native peptides. In vivo, PWT2-SP displayed higher potency and a marked prolongation of action, compared with SP.

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“…304 Coupling of the light chain of BoNT-A with substance P showed a beneficial role in treating chronic pain after intrathecal delivery. 305 …”

Section: Survey Of Current Targets Of Pain Therapeuticsmentioning

confidence: 99%

Basic/Translational Development of Forthcoming Opioid- and Nonopioid-Targeted Pain Therapeutics

Knezevic

Yekkirala

Yaksh

2017

Anesthesia &Amp; Analgesia

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Opioids Opioids represent an efficacious therapeutic modality for some, but not all pain states. Singular reliance on opioid therapy for pain management, has limitations and abuse potential has deleterious consequences for patient and society. Our understanding of pain biology has yielded insights and opportunities for alternatives to conventional opioid agonists. The aim is to have efficacious therapies, with acceptable side effect profiles and minimal abuse potential, which is to say an absence of re-enforcing activity in the absence of a pain state. The present work provides a non-exclusive overview of current drug targets and potential future directions of research and development. We discuss channels activators and blockers, including: sodium channel blockers, potassium channel activators and calcium channel blockers; glutamate receptor targeted agents, including: NMDA, AMPA and metabotropic receptors). Further, we discuss therapeutics targeted at GABA, alpha2 adrenergic and opioid receptors. We also considered antagonists of angiotensin 2 and Toll receptors, and agonists/antagonists of adenosine, purine receptors. And cannabinoids. Novel targets considered are those focusing on lipid mediators and anti-inflammatory cytokines. Of interest is development of novel targeting strategies which produce long-term alterations in pain signaling, including viral transfection and toxins. We consider issues in the development of drugable molecules, including preclinical screening. While there are examples of successful translation, mechanistically promising pre-clinical candidates may unexpectedly fail during clinical trials because the preclinical models may not recapitulate the particular human pain condition being addressed. Molecular target characterization can diminish the disconnect between preclinical and humans’ targets, which should assist in developing non-addictive analgesics.

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Anti-nociceptive effect of a conjugate of substance P and light chain of botulinum neurotoxin type A

Cited by 48 publications

References 42 publications

Therapeutic use of botulinum toxin in pain treatment

Therapeutic use of botulinum toxin in pain treatment

Pharmacological characterization of tachykinin tetrabranched derivatives

Basic/Translational Development of Forthcoming Opioid- and Nonopioid-Targeted Pain Therapeutics

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