Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In addition to inhibition of acetylcholine release in the neuromuscular junction botulinum toxin type A (BoNT-A) also inhibits the release of mediators involved in pain perception. We have investigated the effect of two types of BoNT-A on mechanical hyperalgesia in the rat models of carrageenan-induced hyperalgesia and of paclitaxel-induced peripheral neuropathy. A subplantar (s.p.) injection of BoNT-A in the ipsilateral hindpaw 3 days before carrageenan administration reduced hypersensitivity. Dysport and Botox elicited comparable antihyperalgesic effects. Dysport up to 30 U/kg and Botox up to 20 U/kg did not impair the rat withdrawal nociceptive reflex or the locomotor performance as assessed by the rotarod test. Intraperitoneal administration of the skeletal muscle relaxant dantrolene produced, in contrast to BoNT-A, more motor impairment than analgesia. Paclitaxel treatment resulted in a peripheral neuropathy that affected the two hindpaws. Injection of 20 U/kg (s.p.) Dysport produced a significant antihyperalgesic effect in the injected paw of neuropathic animals 3 days after administration. Unexpectedly, a similar analgesic effect was observed in the contralateral paw. The same results were also observed when Botox was used instead of Dysport. In contrast, a contralateral administration of Dysport in the carrageenan test was ineffective. We conclude that BoNT-A elicits antinociceptive effects independent of the effects on muscular relaxation. Our results suggest that different mechanisms of action are responsible for the effect of BoNT-A in inflammatory and peripheral polyneuropathic rat models.
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PMID:Different antinociceptive effects of botulinum toxin type A in inflammatory and peripheral polyneuropathic rat models. 1957 81

The afferent innervation of the urinary bladder consists primarily of small myelinated (Adelta) and unmyelinated (C-fiber) axons that respond to chemical and mechanical stimuli. Immunochemical studies indicate that bladder afferent neurons synthesize several putative neurotransmitters, including neuropeptides, glutamic acid, aspartic acid, and nitric oxide. The afferent neurons also express various types of receptors and ion channels, including transient receptor potential channels, purinergic, muscarinic, endothelin, neurotrophic factor, and estrogen receptors. Patch-clamp recordings in dissociated bladder afferent neurons and recordings of bladder afferent nerve activity have revealed that activation of many of these receptors enhances neuronal excitability. Afferent nerves can respond to chemicals present in urine as well as chemicals released in the bladder wall from nerves, smooth muscle, inflammatory cells, and epithelial cells lining the bladder lumen. Pathological conditions alter the chemical and electrical properties of bladder afferent pathways, leading to urinary urgency, increased voiding frequency, nocturia, urinary incontinence, and pain. Neurotrophic factors have been implicated in the pathophysiological mechanisms underlying the sensitization of bladder afferent nerves. Neurotoxins such as capsaicin, resiniferatoxin, and botulinum neurotoxin that target sensory nerves are useful in treating disorders of the lower urinary tract.
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PMID:Afferent nerve regulation of bladder function in health and disease. 1965 6

Release of inflammatory pain mediators from peripheral sensory afferent endings contributes to the development of a positive feedback cycle resulting in chronic inflammation and pain. Botulinum neurotoxin type A (BoNT-A) blocks exocytosis of neurotransmitters and may therefore block the release of pain modulators in the periphery. Subcutaneous administration of BoNT-A (2.5, 5 and 10U) reduced plasma extravasation (PE) caused by electrical stimulation of the saphenous nerve or capsaicin in the rat hindpaw skin (ANOVA, Post hoc Tukey, p<0.05, n=6). Subcutaneous BoNT-A also reduced blood flow changes evoked by saphenous nerve stimulation (ANOVA, Post hoc Tukey, p<0.05, n=6). Subcutaneous BoNT-A had no effect on PE induced by local injection of substance P (SP) or vasodilation induced by local CGRP injection. Although BoNT-A is an effective treatment for a wide range of painful conditions, the toxin's large size necessitates that it be injected at numerous sites. We found that a short synthetic peptide (TD-1) can facilitate effective transdermal delivery of BoNT-A through intact skin. Coadministration of TD-1 and BoNT-A to the hindpaw skin resulted in a significant reduction in PE evoked by electrical stimulation. The findings show that BoNT-A can be administered subcutaneously or topically with a novel transdermal delivery peptide to reduce inflammation produced by activating nociceptors in the skin. Peptide-mediated delivery of BoNT-A is an easy and non-invasive way of administering the toxin that may prove to be useful in clinical practice.
Pain 2010 May
PMID:Peptide-mediated transdermal delivery of botulinum neurotoxin type A reduces neurogenic inflammation in the skin. 2022 89

Response rate (RR) and mean improvement (MI) in the pain subscale of the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS-PS) from two placebo-controlled studies and one comparator-controlled study were evaluated to examine the effect of rimabotulinumtoxinB (BoNT-B) on cervical dystonia (CD) pain. Subjects receiving either of two doses of BoNT-B in the AN072-301 trial had an RR of 66% and 58% compared with 23% for placebo (p < .05). Subjects receiving BoNT-B in the AN072-302 trial had an RR of 49% compared with 19% for placebo (p < .05). Subjects receiving BoNT-B in the AN072-402 comparator-controlled trial had a significantly higher RR than those treated with BoNT-A (59% vs. 36%; p < .05). Additionally, subjects treated with BoNT-B in these placebo-controlled trials had significantly larger MIs than those treated with placebo (4.3 and 3.7 vs. 0.5 for AN072-301 and 3.6 vs. 0.1 for AN072-302; p < .05). Subjects treated with BoNT-B in the comparator-controlled trial demonstrated a numerically larger MI than those treated with BoNT-A (2.6 vs. 1.8; p = .1651). These results support the consideration of BoNT-B as an effective first-line botulinum toxin treatment for patients with CD who list pain as a primary complaint.
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PMID:RimabotulinumtoxinB effects on pain associated with cervical dystonia: results of placebo and comparator-controlled studies. 2037 78

Clostridial neurotoxins from the botulinum neurotoxin (BoNT) family are protein complexes, derived from the bacterium Clostridium botulinum, which potently inhibit acetylcholine release and result in a reversible blockade of the neuromuscular junction. This feature led to the clinical development of BoNT-A for a number of neuromuscular disorders. BoNT-A toxins are commercially available as three different preparations: Dysport/Azzalure, Botox/Vistabel, and Xeomin/Bocouture. Although BoNT-A preparations have not yet been approved for the treatment of pain, a substantial body of preclinical and clinical evidence shows that BoNT-A is effective in treating a number of different types of pain. It is thought to exert an analgesic effect both via muscle-relaxant properties and also directly, via inhibition of nociceptive neuropeptides. This review explores the mechanistic basis of this analgesic effect, summarizing current knowledge of the structure-function relationship of BoNT and discussing effects on both motor and pain neurons. For a complete picture of the analgesic properties of BoNT-A, clinical evidence of efficacy in myofascial pain and neuropathic pain is considered in tandem with a mechanistic rationale for activity. Patients experiencing chronic pain are clear candidates for treatment with a modified clostridial endopeptidase that would provide enduring inhibition of neurotransmitter release. A strong preclinical evidence base underpins the concept that re-engineering of BoNT could be used to enhance the analgesic potential of this neurotoxin, and it is hoped that the first clinical studies examining re-engineered BoNT-A will confirm this potential.
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PMID:Re-engineering clostridial neurotoxins for the treatment of chronic pain: current status and future prospects. 2046 83

Chronic perineal pain is an often encountered problem, which produces a great degree of functional impairment and frustration to the patient and a challenge to the treating physician. The reason for this problem is that the region contains diverse anatomic structures with mixed somatic, visceral and autonomic innervations affecting bladder and bowel control and sexual function. A blockade of nociceptive and sympathetic supply to the perineal region, supplied through the ganglion impar has been shown to benefit patients with chronic perineal pain. Several options to this block have been described that chemical neurolysis, radiofrequency ablation etc. Although the analgesic effect of Botulinum toxin type A (BoNT-A) has long been considered secondary to its action for muscle relaxation, BoNT-A also affects the release of the neurotransmitters that are involved in pain perception. We describe a patient who was successfully given ganglion impar block with BoNT-A.
Korean J Pain 2010 Mar
PMID:Ganglion impar block with botulinum toxin type a for chronic perineal pain -a case report-. 2055 77

Lower limb disorders of movement and muscle tone in adults significantly impact quality of life. The management of the patient with hypertonia is complex and requires a multidisciplinary team working with the patient and family/carers. Botulinum neurotoxin type A (BoNT-A) has been used as a component of this management to reduce lower limb hypertonia, increase passive range of motion and reduce associated pain and requirements for bracing. Adjunctive treatments to augment the effect of BoNT-A include electrical muscle stimulation of the injected muscles and stretching. When determining suitability for injection, the patient's main goals for intervention need to be established. Muscle overactivity must be distinguished from contracture, and the effect of underlying muscle weakness taken into account. Explanation of the injection process, potential adverse effects and post-injection interventions is essential. Assessment at baseline and post-treatment of impairments such as hypertonia, range of motion and muscle spasm are appropriate; however, the Goal Attainment Scale and other validated patient-centred scales can also be useful to assess therapy outcomes. In the future, initiatives should be directed towards examining the effectiveness of BoNT treatment to assist with achievement of functional and participation goals in adults with hypertonia and dystonia affecting the lower limb.
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PMID:Botulinum toxin assessment, intervention and aftercare for lower limb disorders of movement and muscle tone in adults: international consensus statement. 2063 79

Evidence is emerging for the use of botulinum neurotoxin type-A (BoNT-A) for niche indications including pain independent of spasticity. Pain indications such as chronic nociceptive back pain, piriformis syndrome, chronic myofascial pain, pelvic pain, complex regional pain syndrome, facial pain and neuropathic pain are outlined in this paper. Of these, class I evidence is available for the treatment of chronic nociceptive low back pain, piriformis syndrome, myofascial pain, facial pain, neuropathic pain and plantar fasciitis. Peri-operative use of BoNT-A is emerging, with indications including planning for surgery and facilitating surgery, as well as healing and improving analgesia post-operatively. Evidence is limited, although there are some reports that clinicians are successfully using BoNT-A peri-operatively. There is class I evidence showing pre-operative use of BoNT-A has a beneficial effect on outcomes following adductor-release surgery. The use of BoNT for treatment of tremor, other than neck tremor in the setting of cervical dystonia, including evidence for upper limb tremor, cranial tremor and non-dystonic neck tremor is reviewed. The evidence is variable at this stage, and further study is required to develop definitive recommendations for the clinical utility of BoNT-A for these indications.
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PMID:Botulinum toxin assessment, intervention and aftercare for paediatric and adult niche indications including pain: international consensus statement. 2063 83

Blockade of neurotransmitter release by botulinum neurotoxin type A (BoNT(A)) underlies the severe neuroparalytic symptoms of human botulism, which can last a few years. The structural basis for this remarkable persistence remains unclear. Herein, recombinant BoNT(A) was found to match the neurotoxicity of that from Clostridium botulinum, producing persistent cleavage of synaptosomal-associated protein of 25 kDa (SNAP-25) and neuromuscular paralysis. When two leucines near the C terminus of the protease light chain of A (LC(A)) were mutated, its inhibition of exocytosis was followed by fast recovery of intact SNAP-25 in cerebellar neurons and neuromuscular transmission in vivo. Deletion of 6-7 N terminus residues diminished BoNT(A) activity but did not alter the longevity of its SNAP-25 cleavage and neuromuscular paralysis. Furthermore, genetically fusing LC(E) to a BoNT(A) enzymically inactive mutant (BoTIM(A)) yielded a novel LC(E)-BoTIM(A) protein that targets neurons, and the BoTIM(A) moiety also delivers and stabilizes the inhibitory LC(E), giving a potent and persistent cleavage of SNAP-25 with associated neuromuscular paralysis. Moreover, its neurotropism was extended to sensory neurons normally insensitive to BoNT(E). LC(E-)BoTIM(A)(AA) with the above-identified dileucine mutated gave transient neuromuscular paralysis similar to BoNT(E), reaffirming that these residues are critical for the persistent action of LC(E)-BoTIM(A) as well as BoNT(A). LC(E)-BoTIM(A) inhibited release of calcitonin gene-related peptide from sensory neurons mediated by transient receptor potential vanilloid type 1 and attenuated capsaicin-evoked nociceptive behavior in rats, following intraplantar injection. Thus, a long acting, versatile composite toxin has been developed with therapeutic potential for pain and conditions caused by overactive cholinergic nerves.
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PMID:A dileucine in the protease of botulinum toxin A underlies its long-lived neuroparalysis: transfer of longevity to a novel potential therapeutic. 2113 36

Botulinum (BoNT) toxin has been used for its muscle-paralyzing action in conditions such as treatment of wrinkles, cervical dystonia and blephrospasm. There is preclinical and emerging clinical evidence of another mechanism of action of BoNT, namely, an antinociceptive action. In this review, we provide an evidence-based review of clinical studies of BoNT in osteoarticular conditions, such as osteoarthritis, tennis elbow, low back pain, and hand pain. Many randomized controlled trials (RCTs) found evidence of short-term efficacy of an injection of BoNT in relief of pain, and in some cases, improvement of function and quality of life. However, more clinical trials are needed to better define the clinical use of BoNT for treatment of refractory osteoarticular pain.
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PMID:Botulinum toxin therapy for osteoarticular pain: an evidence-based review. 2130 30


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