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1.
J Neural Transm (Vienna) ; 123(12): 1415-1421, 2016 12.
Article in English | MEDLINE | ID: mdl-27586162

ABSTRACT

In the motor system, botulinum toxin type A (BoNT/A) actions were classically attributed to its well-known peripheral anticholinergic actions in neuromuscular junctions. However, the enzymatic activity of BoNT/A, assessed by the detection of cleaved synaptosomal-associated protein 25 (SNAP-25), was recently detected in motor and sensory regions of the brainstem and spinal cord after toxin peripheral injection in rodents. In sensory regions, the function of BoNT/A activity is associated with its antinociceptive effects, while in motor regions we only know that BoNT/A activity is present. Is it possible that BoNT/A presence in central motor nuclei is without any function? In this brief review, we analyze this question. Limited data available in the literature warrant further investigations of BoNT/A actions in motor nervous system.


Subject(s)
Botulinum Toxins, Type A/pharmacology , Nervous System , Animals , Botulinum Toxins, Type A/metabolism , Gene Expression/drug effects , Humans , Motor Neurons/drug effects , Motor Neurons/physiology , Nervous System/cytology , Nervous System/drug effects , Nervous System/metabolism , Neural Pathways/drug effects , Neural Pathways/physiology
2.
Neurosci Lett ; 617: 213-7, 2016 Mar 23.
Article in English | MEDLINE | ID: mdl-26876447

ABSTRACT

Despite its toxicity, botulinum neurotoxin type A (BTX-A) is a valuable therapeutic agent for several motor, autonomic and pain disorders. Numerous studies have described its peripheral as well as central effects. Using reversed-phase High Performance Liquid Chromatography with Electrochemical Detection (HPLC-ED) and gradient elution, we quantified the concentrations of dopamine (DA), noradrenaline (NA), serotonin (5-HT) and their metabolites in 10 brain regions, ipsilateral and contralateral from the site of unilateral BTX-A administration (5 U/kg) into the rat whisker pad. In regions associated with nociception and pain processing we also examined possible BTX-A effects in combination with formalin-induced inflammatory orofacial pain. The dominant BTX-A effects on the monoamines and their metabolites were insignificant. The only significant increase caused by BTX-A alone was that of NA in striatum and serotonin in hypothalamus. While antinociceptive effects of BTX-A are most probably not related to central monoamine concentrations, the localized increased NA and 5-HT concentrations might play a role in reported BTX-A efficacy for the treatment of depression.


Subject(s)
Biogenic Monoamines/metabolism , Botulinum Toxins, Type A/pharmacology , Brain/drug effects , Amygdala/drug effects , Amygdala/metabolism , Animals , Brain/metabolism , Corpus Striatum/drug effects , Corpus Striatum/metabolism , Face , Hypothalamus/drug effects , Hypothalamus/metabolism , Injections , Male , Rats, Wistar , Trigeminal Nuclei/drug effects , Trigeminal Nuclei/metabolism
3.
J Neural Transm (Vienna) ; 121(5): 555-63, 2014 May.
Article in English | MEDLINE | ID: mdl-24366531

ABSTRACT

Up to now, dural neurogenic inflammation (DNI) has been studied primarily as a part of migraine pain pathophysiology. A recent study from our laboratory demonstrated the occurrence of DNI in response to peripheral trigeminal nerve injury. In this report, we characterize the occurrence of DNI after different peripheral nerve injuries in and outside of the trigeminal region. We have used the infraorbital nerve constriction injury model (IoNC) as a model of trigeminal neuropathic pain. Greater occipital nerve constriction injury (GoNC), partial transection of the sciatic nerve (ScNT) and sciatic nerve constriction injury (SCI) were employed to characterize the occurrence of DNI in response to nerve injury outside of the trigeminal region. DNI was measured as colorimetric absorbance of Evans blue plasma protein complexes. In addition, cellular inflammatory response in dural tissue was histologically examined in IoNC and SCI models. In comparison to the strong DNI evoked by IoNC, a smaller but significant DNI has been observed following the GoNC. However, DNI has not been observed either in cranial or in lumbar dura following ScNT and SCI. Histological evidence has demonstrated a dural proinflammatory cell infiltration in the IoNC model, which is in contrast to the SCI model. Inflammatory cell types (lymphocytes, plasma cells, and monocytes) have indicated the presence of sterile cellular inflammatory response in the IoNC model. To our knowledge, this is the first observation that the DNI evoked by peripheral neuropathic pain is specific to the trigeminal area and the adjacent occipital area. DNI after peripheral nerve injury consists of both plasma protein extravasation and proinflammatory cell infiltration.


Subject(s)
Dura Mater/immunology , Neuralgia/complications , Neurogenic Inflammation/etiology , Peripheral Nerve Injuries/complications , Trigeminal Nerve Injuries/complications , Animals , Disease Models, Animal , Dura Mater/pathology , Hyperalgesia/complications , Lumbar Vertebrae , Male , Rats, Wistar , Sciatic Nerve/injuries , Skull , Touch
4.
Neuropharmacology ; 70: 331-7, 2013 Jul.
Article in English | MEDLINE | ID: mdl-23499661

ABSTRACT

Botulinum toxin A (BTX-A) is approved for treatment of chronic migraine and has been investigated in various other painful conditions. Recent evidence demonstrated retrograde axonal transport and suggested the involvement of CNS in antinociceptive effect of BTX-A. However, the mechanism of BTX-A central antinociceptive action is unknown. In this study we investigated the potential role of opioid receptors in BTX-A's antinociceptive activity. In formalin-induced inflammatory pain we assessed the effect of opioid antagonists on antinociceptive activity of BTX-A. Naltrexone was injected subcutaneously (0.02-2 mg/kg) or intrathecally (0.07 µg/10 µl-350 µg/10 µl), while selective µ-antagonist naloxonazine was administered intraperitoneally (5 mg/kg) prior to nociceptive testing. The influence of naltrexone (2 mg/kg s.c.) on BTX-A antinociceptive activity was examined additionally in an experimental neuropathy induced by partial sciatic nerve transection. To investigate the effects of naltrexone and BTX-A on neuronal activation in spinal cord, c-Fos expression was immunohistochemically examined in a model of formalin-induced pain. Antinociceptive effects of BTX-A in formalin and sciatic nerve transection-induced pain were prevented by non-selective opioid antagonist naltrexone. Similarly, BTX-A-induced pain reduction was abolished by low dose of intrathecal naltrexone and by selective µ-antagonist naloxonazine. BTX-A-induced decrease in dorsal horn c-Fos expression was prevented by naltrexone. Prevention of BTX-A effects on pain and c-Fos expression by opioid antagonists suggest that the central antinociceptive action of BTX-A might be associated with the activity of endogenous opioid system (involving µ-opioid receptor). These results provide first insights into the mechanism of BTX-A's central antinociceptive activity.


Subject(s)
Analgesics/pharmacology , Botulinum Toxins, Type A/pharmacology , Receptors, Opioid, mu/agonists , Receptors, Opioid, mu/antagonists & inhibitors , Analgesics/antagonists & inhibitors , Animals , Botulinum Toxins, Type A/antagonists & inhibitors , Dose-Response Relationship, Drug , Drug Interactions , Male , Naloxone/analogs & derivatives , Naloxone/pharmacology , Naltrexone/pharmacology , Narcotic Antagonists/pharmacology , Posterior Horn Cells/drug effects , Posterior Horn Cells/metabolism , Proto-Oncogene Proteins c-fos/metabolism , Rats
5.
Neuroscience ; 186: 201-7, 2011 Jul 14.
Article in English | MEDLINE | ID: mdl-21539899

ABSTRACT

Botulinum toxin A (BTX-A) is approved for treatment of different cholinergic hyperactivity disorders, and, recently, migraine headache. Although suggested to act only locally, novel observations demonstrated bilateral reduction of pain after unilateral toxin injection, and proposed retrograde axonal transport, presumably in sensory neurons. However, up to now, axonal transport of BTX-A from periphery to CNS was identified only in motoneurons, but with unknown significance. We assessed the effects of low doses of BTX-A injected into the rat whisker pad (3.5 U/kg) or into the sensory trigeminal ganglion (1 U/kg) on formalin-induced facial pain. Axonal transport was prevented by colchicine injection into the trigeminal ganglion (5 mM, 2 µl). To find the possible site of action of axonally transported BTX-A, we employed immunohistochemical labeling of BTX-A-truncated synaptosomal-associated protein 25 (SNAP-25) in medullary dorsal horn of trigeminal nucleus caudalis after toxin injection into the whisker pad. Both peripheral and intraganglionic BTX-A reduce phase II of formalin-induced pain. Antinociceptive effect of BTX-A was prevented completely by colchicine. BTX-A-truncated SNAP-25 in medullary dorsal horn (spinal trigeminal nucleus) was evident 3 days following the peripheral treatment, even with low dose applied (3.5 U/kg). Presented data provide the first evidence that axonal transport of BTX-A, obligatory for its antinociceptive effects, occurs via sensory neurons and is directed to sensory nociceptive nuclei in the CNS.


Subject(s)
Behavior, Animal/physiology , Botulinum Toxins, Type A/physiology , Facial Pain/metabolism , Nociceptors/metabolism , Trigeminal Nerve/physiology , Analgesics/pharmacology , Animals , Axonal Transport/drug effects , Axonal Transport/physiology , Behavior, Animal/drug effects , Central Nervous System/drug effects , Central Nervous System/physiology , Facial Pain/drug therapy , Facial Pain/physiopathology , Immunohistochemistry , Male , Nociceptors/drug effects , Nociceptors/physiology , Rats , Rats, Wistar , Sensory Receptor Cells/drug effects , Sensory Receptor Cells/physiology , Trigeminal Nerve/drug effects
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