Current status and future directions of botulinum neurotoxins for targeting pain processing.

Current evidence suggests that botulinum neurotoxins (BoNTs) A1 and B1, given locally into peripheral tissues such as skin, muscles, and joints, alter nociceptive processing otherwise initiated by inflammation or nerve injury in animal models and humans. Recent data indicate that such locally delivered BoNTs exert not only local action on sensory afferent terminals but undergo transport to central afferent cell bodies (dorsal root ganglia) and spinal dorsal horn terminals, where they cleave SNAREs and block transmitter release. Increasing evidence supports the possibility of a trans-synaptic movement to alter postsynaptic function in neuronal and possibly non-neuronal (glial) cells. The vast majority of these studies have been conducted on BoNT/A1 and BoNT/B1, the only two pharmaceutically developed variants. However, now over 40 different subtypes of botulinum neurotoxins (BoNTs) have been identified. By combining our existing and rapidly growing understanding of BoNT/A1 and /B1 in altering nociceptive processing with explorations of the specific characteristics of the various toxins from this family, we may be able to discover or design novel, effective, and long-lasting pain therapeutics. This review will focus on our current understanding of the molecular mechanisms whereby BoNTs alter pain processing, and future directions in the development of these agents as pain therapeutics

Supraspinal characterization of the thermal grill illusion with fMRI.

BackgroundSimultaneous presentation of non-noxious warm (40°C) and cold (20°C) stimuli in an interlacing fashion results in a transient hot burning noxious sensation (matched at 46°C) known as the thermal grill (TG) illusion. Functional magnetic resonance imaging and psychophysical assessments were utilized to compare the supraspinal events related to the spatial summation effect of three TG presentations: 20°C/20°C (G2020), 20°C/40°C (G2040) and 40°C/40°C (G4040) with corresponding matched thermode stimuli: 20°C (P20), 46°C (P46) and 40°C (P40) and hot pain (HP) stimuli.ResultsFor G2040, the hot burning sensation was only noted during the initial off-line assessment. In comparison to P40, G4040 resulted in an equally enhanced response from all supraspinal regions associated with both pain sensory/discriminatory and noxious modulatory response. In comparison to P20, G2020 presentation resulted in a much earlier diminished/sedative response leading to a statistically significantly (P < 0.01) higher degree of deactivation in modulatory supraspinal areas activated by G4040. Granger Causality Analysis showed that while thalamic activation in HP may cast activation inference in all hot pain related somatosensory, affective and modulatory areas, similar activation in G2040 and G2020 resulted in deactivation inference in the corresponding areas.ConclusionsIn short, the transient TG sensation is caused by a dissociated state derived from non-noxious warm and cold spatial summation interaction. The observed central dissociated state may share some parallels in certain chronic neuropathic pain states

Endovascular catheter ablation of ventricular tachycardia in a patient with a surgically repaired congenital left ventricular aneurysm

We present a patient with a congenital left ventricular aneurysm who visited our outpatient clinic for a routine check-up and, during this visit, lost consciousness due to sustained ventricular tachycardia. In our patient, endocardial mapping revealed extensive conduction abnormalities, and successful ablation was accomplished at the endocardial surface

Intrathecal clonidine in the neonatal rat: dose-dependent analgesia and evaluation of spinal apoptosis and toxicity

Neuraxial clonidine is used for perioperative analgesia in children of all ages. Preclinical studies in the postnatal rat allow comparison of the relative toxicity and safety of spinal analgesics throughout postnatal development

Evaluation of neurotoxicity and long-term function and behavior following intrathecal 1 % 2-chloroprocaine in juvenile rats

Spinally-administered local anesthetics provide effective perioperative anesthesia and/or analgesia for children of all ages. New preparations and drugs require preclinical safety testing in developmental models. We evaluated age-dependent efficacy and safety following 1 % preservative-free 2-chloroprocaine (2-CP) in juvenile Sprague-Dawley rats. Percutaneous lumbar intrathecal 2-CP was administered at postnatal day (P)7, 14 or 21. Mechanical withdrawal threshold pre- and post-injection evaluated the degree and duration of sensory block, compared to intrathecal saline and naive controls. Tissue analyses one- or seven-days following injection included histopathology of spinal cord, cauda equina and brain sections, and quantification of neuronal apoptosis and glial reactivity in lumbar spinal cord. Following intrathecal 2-CP or saline at P7, outcomes assessed between P30 and P72 included: spinal reflex sensitivity (hindlimb thermal latency, mechanical threshold); social approach (novel rat versus object); locomotor activity and anxiety (open field with brightly-lit center); exploratory behavior (rearings, holepoking); sensorimotor gating (acoustic startle, prepulse inhibition); and learning (Morris Water Maze). Maximum tolerated doses of intrathecal 2-CP varied with age (1.0 μL/g at P7, 0.75 μL/g at P14, 0.5 μL/g at P21) and produced motor and sensory block for 10−15 min. Tissue analyses found no significant differences across intrathecal 2-CP, saline or naïve groups. Adult behavioral measures showed expected sex-dependent differences, that did not differ between 2-CP and saline groups. Single maximum tolerated in vivo doses of intrathecal 2-CP produced reversible spinal anesthesia in juvenile rodents without detectable evidence of developmental neurotoxicity. Current results cannot be extrapolated to repeated dosing or prolonged infusion