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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Botulinum neurotoxins are the most potent acute lethal toxins known, and yet for the last two decades they, and in particular serotype A, have found increasing use in the clinical treatment of diseases or conditions involving neuromuscular or autonomic neuronal transmission. The neurotoxins work by inhibiting the release of acetylcholine from peripheral cholinergic nerve terminals. More recently, the effects on non-cholinergic pathways have been identified, and this has led to an increase in the diseases and syndromes for which botulinum neurotoxins have been found to have clinical utility. In particular, botulinum neurotoxins have been demonstrated to potentially benefit a range of chronic pain syndromes. With the description in the last decade of the biochemical basis of neurotoxin action and the tertiary structure of the toxin molecule, the possibility of designing novel agents utilising selected aspects of toxin function has arisen. This possibility has been pursued in the context of pain relief with the description of a novel hybrid protein derived from botulinum neurotoxin type A, LH(N)/A-ECL, able to selectively target nociceptive afferent neurons and inhibit the release of neurotransmitters involved in pain transmission. This novel derivative of botulinum neurotoxin type A demonstrates prolonged analgesic activity in vivo. This review will consider the evidence for the analgesic properties of the botulinum neurotoxins and their suitability as the basis for novel therapeutic proteins. The general concept of deriving novel therapeutic molecules from the neurotoxins will also be considered.
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PMID:The analgesic potential of clostridial neurotoxin derivatives. 1550 Mar 91

Several in vitro and in vivo investigations have shown that botulinum toxin A (BoNT/A) can inhibit the release of substance P and excitatory amino acids. Recently, a marked antinociceptive effect of BoNT/A and inhibition of glutamate release was observed in an animal pain model with inflammatory sensitization. In the present study, we tested the antiinflammatory and antihyperalgetic effect of BoNT/A in a well-characterized human inflammatory pain model. Using a randomized, double-blind, paired study design, we compared the effects of 100 mouse units of BoNT/A versus pure saline. Thermal and mechanical pain testings and superficial skin blood flow measurements were performed at baseline, at 48 h (in normal skin), and at 72 h (in inflamed skin) thereafter. Ultraviolet B irradiation resulted in a local inflammation with significant primary and secondary hyperalgesia. However, despite the evidence of efficacy on sudomotor function, BoNT/A had no effect on pain measures in either normal or inflamed skin. Signs of inflammation and primary and secondary hyperalgesia were found to be unaffected by BoNT. We have confirmed that BoNT/A has no direct effect on acute, noninflammatory pain. Furthermore, despite highly promising data from animal research, we have not observed antiinflammatory or antinociceptive effects of BoNT/A in human inflammatory pain.
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PMID:A lack of antinociceptive or antiinflammatory effect of botulinum toxin A in an inflammatory human pain model. 1642 52

Neurotoxins affecting neuroexocytosis can represent an innovative pharmacological approach to the investigation of neural mechanisms of pain. Our interest has been focused on the use of botulinum neurotoxins (BoNTs), whose peripheral effects are extensively documented, while the effects on the central nervous system are much less clear. We have investigated both peripheral (sc into the hindpaw) and central (icv) effects of two BoNTs isoforms, BoNT/A and BoNT/B, on inflammatory pain. BoNT/A (sc: 0.937-15; icv: 0.937-3.75 pgtox/mouse) and BoNT/B (sc: 3.75, 7.5; icv: 1.875, 3.75 pgtox/mouse) were injected in CD1 mice and tested in the formalin test 3 days later. Licking response, as index of pain, and behavioral parameters, such as general activity and grooming, were recorded for 40 min during the test. BoNT/A partially affects the licking response in the second phase of formalin test in a similar magnitude of attenuation whether peripherally or centrally administered. BoNT/A does not significantly affect licking behavior during the first phase of the test. Peripheral administration of BoNT/B attenuates the licking response during the first phase not modifying the second phase, while the icv administration has hyperalgesic effect on the interphase of the formalin test. General activity and grooming behavior are not affected either by peripheral or by central administration of BoNTs. Our results show for the first time a central effect of BoNTs that differently modulate inflammatory pain depending both on serotype and on route of administration. Such data suggest BoNTs as a useful tool in the studies aimed at the comprehension of the mechanisms of inflammatory pain.
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PMID:Botulinum neurotoxins and formalin-induced pain: central vs. peripheral effects in mice. 1652 62

The trigeminovascular system is involved in migraine. Efficacy of Botulinum Toxin type A (BoNT-A) in migraine has been investigated in clinical studies but the mechanism of action remains unexplored. It is hypothesized that BoNT-A inhibits peripheral sensitization of nociceptive fibers and indirectly reduces central sensitization. We examined the effect of intramuscular injection of BoNT-A on an experimental human model of trigeminal sensitization induced by intradermal capsaicin injection to the forehead. BoNT-A (BOTOX) or saline was injected intramuscularly in precranial, neck and shoulder muscles to 32 healthy male volunteers in a double blind-randomized manner. Intradermally capsaicin-induced pain, flare and secondary hyperalgesia were obtained before and 1, 4 and 8 weeks after the above treatments. A significant suppressive effect of BoNT-A on pain, flare and hyperalgesia area was observed. The pain intensity area was significantly smaller in BoNT-A group (9.16+/-0.83 cm x s) compared to saline group (15.41+/-0.83cm x s) (P=0.011). The flare area was also reduced significantly in BoNT-A group (29.81+/-0.69 cm2) compared to saline group (39.71+/-0.69 cm2) (P<0.001). Similarly, the mean area of secondary hyperalgesia was significantly smaller in BoNT-A group (4.25+/-0.91 cm2) compared to saline group (7.03+/-0.91 cm2) (P=0.040). Post hoc analysis showed significant differences across the trials with a remarkable suppression effect of BoNT-A on capsaicin-induced sensory and vasomotor reactions as early as week1 (P<0.001). BoNT-A presented suppressive effects on the trigeminal/cervical nociceptive system activated by intradermal injection of capsaicin to the forehead. The effects are suggested to be caused by a local peripheral effect of BoNT-A on cutaneous nociceptors.
Pain 2006 Jun
PMID:The effects of Botulinum Toxin type A on capsaicin-evoked pain, flare, and secondary hyperalgesia in an experimental human model of trigeminal sensitization. 1667 61

Botulinum type A toxin (BoNT-A) has antinociceptive and muscle-relaxant properties and may help relieve the symptoms of myofascial pain syndrome. In this study we evaluated the efficacy and tolerability of BoNT-A (Dysport) in patients with myofascial pain syndrome of the upper back. We conducted a prospective, randomized, double-blind, placebo-controlled, 12-week, multicentre study. Patients with moderate-to-severe myofascial pain syndrome affecting cervical and/or shoulder muscles (10 trigger points, disease duration 6-24 months) were randomized to Dysport or saline. Injections were made into the 10 most tender trigger points (40 units per site). The primary outcome was the proportion of patients with mild or no pain at week 5. Secondary outcomes included changes in pain intensity and the number of pain-free days per week. Tolerability and safety were also assessed. At week 5, significantly more patients in the Dysport group reported mild or no pain (51%), compared with the patients in the placebo group (26%; p=0.002). Compared with placebo, Dysport resulted in a significantly greater change from baseline in pain intensity during weeks 5-8 (p<0.05), and significantly fewer days per week without pain between weeks 5 and 12 (p=0.036). Treatment was well tolerated, with most side effects resolving within 8 weeks. In conclusion, in patients with upper back myofascial pain syndrome, injections of 400 Ipsen units of Dysport at 10 individualised trigger points significantly improved pain levels 4-6 weeks after treatment. Injections were well tolerated.
Pain 2006 Nov
PMID:Efficacy and safety of a single botulinum type A toxin complex treatment (Dysport) for the relief of upper back myofascial pain syndrome: results from a randomized double-blind placebo-controlled multicentre study. 1753 40

Among various machineries occurring in the experimental neuropathic pain model, there exists the loss of pain transmission through C-fiber neurons as well as the hypersensitivity through A-fibers. The current study reveals that molecular machineries underlying the latter hypersensitivity are derived from the events through LPA1 receptor and its downstream RhoA-activation following peripheral nerve injury. The loss of C-fiber responses, which are mediated by spinal substance P (SP) pain transmission was observed with the nociceptive flexor responses by intraplantar injection of SP in nerve-injured mice. The immunohistochemistry revealed that SP signal in the dorsal horn was markedly reduced in such mice. All these changes were completely abolished in LPA1-/- mice or by the pretreatment with BoNT/C3, a RhoA inhibitor. In addition, the loss of C-fiber responses and the down-regulation of spinal SP signal induced by single intrathecal LPA injection were also abolished in such treatments. All these results suggest that the loss of pain transmission through polymodal C-fiber neurons is also mediated by the LPA1 activation following nerve injury.
Mol Pain 2006 Aug 16
PMID:Loss of spinal substance P pain transmission under the condition of LPA1 receptor-mediated neuropathic pain. 1691 35

Cervical dystonia (CD) is due to neck-muscle spasms that cause pain and involuntary contractions resulting in abnormal neck movements and posture. Symptoms can be relieved by injecting the affected muscle with a botulinum neurotoxin (BoNT, usually type A or type B). The therapeutic benefits are impermanent and toxin injections need to be repeated every 3-6 months. In a very small percentage of patients (less with BoNT/A than with BoNT/B) the treatment elicits blocking anti-toxin antibodies (Abs), which reduce or terminate the patient's responsiveness to further treatment. We have recently mapped (Dolimbek et al., 2006) the CD sera Ab-binding profile using a panel of 60, 19-residue peptides that encompassed the entire H chain sequence 449-1296 and overlapped consecutively by 5 residues. Abs in CD sera bound to one or more of the peptides N25, C10, C15, C20, and C31. This suggested the possibility that binding to these peptides could be used for assay of Abs in CD sera. Data analysis reported here found that Ab binding to these regions showed very significant deviations from the control responses. Of these four peptides, C10 showed the most significant level of separation between patient and control groups (p = 5 x 10(-7)) and the theoretical resolution (i.e., ability to distinguish CD patients from control, see full definition under 'Statistical analysis' in Methods), 84%, was about 4% higher than the least resolved response, C31 (p = 6 x 10(-6), resolution 80%). Since the amounts of Abs bound to a given peptide varied with the patient and not all the patients necessarily recognized all four peptides, there was the possibility that binding to combinations of two or more peptides might give a better discriminatory capability. Using two peptides, C10 plus C31, the resolution improved to 87% (p = 4 x 10(-8)). These two peptides appeared to compliment each other and negate the lower resolution of C31. Combination of three peptides gave resolutions that ranged from 85 (N25 + C15 + C31; p = 2 x 10(-7)) to 88% (C10 + C15 + C31; p = 1 x 10(-8)). Finally, using the data of all four peptides, N25 + C10 + C15 + C31, gave a resolution of 86% (p = 1 x 10(-7)). Although these levels of resolution are somewhat lower than that obtained with whole BoNT/A (resolution 97%; p = 6 x 10(-12)), it may be concluded that the two-peptide combination C10 + C31, or the three-peptide combination C10 + C15 + C31 (affording resolutions of 87 and 88%, respectively) provide a good diagnostic, toxin-free procedure for assay of total specific anti-toxin Abs in BoNT/A-treated CD patients.
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PMID:A peptide-based immunoassay for antibodies against botulinum neurotoxin A. 1698 Dec 47

Lysophosphatidic acid (LPA) causes neuropathic pain with demyelination in sensory fibers. In dorsal root (DR) ex vivo culture, the addition of 0.1 microM LPA caused a characteristic demyelination at 24h in scanning and transmission electron microscopy analyses. Moreover, direct contact between C-fibers due to loss of partition by Schwann cell in Remak bundles was observed. LPA-induced demyelination of DR was concentration-dependent in the range between 0.01 and 1M, and was abolished by BoNT/C3 and Y-27632, a RhoA and Rho kinase inhibitor, respectively. The demyelination was equivalent between the preparations with and without dorsal root ganglion. LPA also caused a down-regulation of myelin proteins, such as myelin basic protein (MBP) and myelin protein zero (MPZ) to approximately 70% of control. All these findings suggest that the demyelination observed in the neuropathic pain due to nerve injury occurs through a direct action of LPA on Schwann cells.
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PMID:LPA-mediated demyelination in ex vivo culture of dorsal root. 1705 57

The seven serotypes (A-G) of botulinum neurotoxin (BoNT) are proteins produced by Clostridium botulinum and have multifunctional abilities: (i) they target cholinergic nerve endings via binding to ecto-acceptors (ii) they undergo endocytosis/translocation and (iii) their light chains act intraneuronally to block acetylcholine release. The fundamental process of quantal transmitter release occurs by Ca2+-regulated exocytosis involving sensitive factor attachment protein-25 (SNAP-25), syntaxin and synaptobrevin. Proteolytic cleavage by BoNT-A of nine amino acids from the C-terminal of SNAP-25 disables its function, causing prolonged muscle weakness. This unique combination of activities underlies the effectiveness of BoNT-A haemagglutinin complex in treating human conditions resulting from hyperactivity at peripheral cholinergic nerve endings. In vivo imaging and immunomicroscopy of murine muscles injected with type A toxin revealed that the extended duration of action results from the longevity of its protease, persistence of the cleaved SNAP-25 and a protracted time course for the remodelling of treated nerve-muscle synapses. In addition, an application in pain management has been indicated by the ability of BoNT to inhibit neuropeptide release from nociceptors, thereby blocking central and peripheral pain sensitization processes. The widespread cellular distribution of SNAP-25 and the diversity of the toxin's neuronal acceptors are being exploited for other therapeutic applications.
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PMID:The structure and mode of action of different botulinum toxins. 1711 44

Botulinum toxin type A (BoNT-A) has been recently suggested as prophylaxis therapy for the treatment of primary headache chronic forms. Several studies on its efficacy are available, but results are often contradictory and not univocal. The effects of BoNTA on chronic forms of both tension- type headache and migraine have been investigated. In this study we introduce our five-year long experience with BoNT-A (Botox, Allergan, Irvine, CA). The employed dosage was 100 U and the Fixed Sites-Fixed Doses (FSFD) protocol was used. The period of study was April 2001 to July 2006. A sum of 1347 patients suffering from chronic daily headache (CDH) were treated. We registered in these patients the number of headache days per month and observed their reduction in relation to the number of injections. The best results were found after 12 months of treatment, with patients being free of attacks 23 days per month. The BoNT-A treatment was safe and well tolerated, as only 1.6% of patients reported adverse events, and they were all mild and transient. In conclusion, BoNT-A therapy appears to be an efficacious new therapeutic choice in the prophylaxis of CDH, especially for patients not responding to previous prophylactic treatments.
J Headache Pain 2006 Dec
PMID:Long-term benefits of botulinum toxin type A (BOTOX) in chronic daily headache: a five-year long experience. 1714 65


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