ABSTRACT
BACKGROUND: Mononeuropathies (MNs: nerve ligation) and polyneuropathies (PNs: cisplatin) produce unilateral and bilateral tactile allodynia, respectively. We examined the effects of intraplantar (IPLT) and intrathecal (IT) botulinum toxin B (BoNT-B) on this allodynia. METHODS: Mice (male c57Bl/6) were prepared with an L5 nerve ligation. Others received cisplatin (IP 2.3 mg/kg/d, every other day for 6 injections). Saline and BoNT-B were administered through the IPLT or IT route. We examined mechanical allodynia (von Frey hairs) before and at intervals after BoNT. As a control, we injected IPLT BoNT-B treated with dithiothreitol to cleave heavy chain from light chain. We measured motor function using acute thermal escape and sensorimotor tests. RESULTS: MN and PN mice showed a persistent ipsilateral and bilateral allodynia, respectively. IPLT BoNT-B resulted in an ipsilateral dorsal horn reduction in the synaptic protein target of BoNT-B (vesicle-associated membrane protein) and a long-lasting (up to approximately 17 days) reversal of allodynia in PN and MN models. The predominant effect after IPLT delivery was ipsilateral to IPLT BoNT. The effects of IPLT BoNT-B in MN mice were blocked by prior reduction of BoNT-B with dithiothreitol. IT BoNT-B in mice with PN resulted in a bilateral reversal of allodynia. With these dosing parameters, hind paw placing and stepping reflexes were unaltered, and there were no changes in thermal escape latencies. After cisplatin, dorsal root ganglions displayed increases in activation transcription factor 3, which were reduced by IT, but not IPLT BoNT-B. CONCLUSIONS: BoNT-B given IPLT and IT yields a long-lasting attenuation of the allodynia in mice displaying MN and PN allodynia.
Subject(s)
Analgesics/administration & dosage , Botulinum Toxins, Type A/administration & dosage , Hyperalgesia/drug therapy , Mononeuropathies/drug therapy , Neuralgia/drug therapy , Pain Threshold/drug effects , Polyneuropathies/drug therapy , Activating Transcription Factor 3/metabolism , Animals , Behavior, Animal/drug effects , Disease Models, Animal , Hyperalgesia/metabolism , Hyperalgesia/physiopathology , Hyperalgesia/psychology , Injections, Spinal , Injections, Subcutaneous , Male , Mice, Inbred C57BL , Mononeuropathies/metabolism , Mononeuropathies/physiopathology , Mononeuropathies/psychology , Motor Activity/drug effects , Neuralgia/metabolism , Neuralgia/physiopathology , Neuralgia/psychology , Pain Measurement , Physical Stimulation , Polyneuropathies/metabolism , Polyneuropathies/physiopathology , Polyneuropathies/psychology , Posterior Horn Cells/drug effects , Posterior Horn Cells/metabolism , Reaction Time/drug effects , Time Factors , Vesicular Transport Proteins/metabolismABSTRACT
Though human pain imaging studies almost always demonstrate activation in the cerebellum, the role of the cerebellum in pain function is not well understood. Here we present results from two studies on the effects of noxious thermal heat and brush applied to the right side of the face in a group of healthy subjects (Group I) and a group of patients with neuropathic pain (Group II) who are more sensitive to both thermal and mechanical stimuli. Statistically significant activations and volumes of activations were defined in the cerebellum. Activated cerebellar structures were identified by colocalization of fMRI activation with the 'MRI Atlas of the Human Cerebellum'. Functional data (obtained using a 3T magnet) were defined in terms of maximum voxels and volume of activation in the cerebellum. Volume maps were then mapped onto two millimeter serial slices taken through the cerebellum in order to identify activation within regions defined by the activation volume. The data indicate that different regions of the cerebellum are involved in acute and chronic pain processing. Heat produces greater contralateral activation compared with brush, while brush resulted in more ipsilateral/bilateral cerebellar activation. Further, innocuous brush stimuli in healthy subjects produced decreased cerebellar activation in lobules concerned with somatosensory processing. The data also suggest a dichotomy of innocuous stimuli/sensorimotor cerebellum activation versus noxious experience/cognitive/limbic cerebellum activation. These results lead us to propose that the cerebellum may modulate the emotional and cognitive experience that distinguishes the perception of pain from the appreciation of innocuous sensory stimulation.
Subject(s)
Cerebellum/physiology , Cerebellum/physiopathology , Mononeuropathies/physiopathology , Nervous System Diseases/physiopathology , Cerebellar Nuclei/pathology , Cerebellar Nuclei/physiology , Cerebellar Nuclei/physiopathology , Cerebellum/pathology , Emotions , Female , Hot Temperature , Humans , Magnetic Resonance Imaging , Male , Mononeuropathies/diagnostic imaging , Mononeuropathies/pathology , Mononeuropathies/psychology , Nervous System Diseases/diagnostic imaging , Nervous System Diseases/pathology , Nervous System Diseases/psychology , Physical Stimulation , Positron-Emission Tomography , Radiography , Reference ValuesABSTRACT
Hypersensitivity of the foot produced by a number of sciatic mononeuropathies was assessed and compared. A new tool was used, the strain-gauge algometer, that delivers a noxious stimulus and gives a direct measurement of the force for paw withdrawal. In addition, we report observations of another alteration of the flexion reflex, persistent hindlimb flexion. The mean mechanical threshold for naive rats was 5.9 +/- 0.97 centinewton (standard deviation). A superficial surgical procedure had no effect on mechanical sensitivity. Sham surgeries and a surgery in which a silicone pellet was glued to the sciatic nerve produced moderate increases in mechanical sensitivity. Interventions that produced the greatest reductions in thresholds were carrageenan neuritis, complete Freund's adjuvant neuritis, and the chronic constriction injury (CCI) model. Mechanical thresholds returned to baseline in 2 weeks in all groups. Neuropathic behaviors (licking and holding the paw after the stimulus) were observed more frequently in the CCI group. Persistent hindlimb flexion was only observed in the CCI group. The results support that midaxonal inflammation is sufficient to induce hyperalgesia. The strain-gauge algometer proved to be efficient and reliable, and calculations support that used as described in this report one can demonstrate changes in paw withdrawal thresholds as small as 15%.
