Articles: neuralgia.
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The search for new ligands to treat neuropathic pain remains a challenge. Recently, oxytocin has emerged as an interesting molecule modulating nociception at central and peripheral levels, but no attempt has been made to evaluate the effect of recurrent oxytocin administration in neuropathic pain. Using male Wistar rats with spinal nerve ligation, we evaluated the effects of recurrent spinal (1 nmol; given by lumbar puncture) or peripheral (31 nmol; given by intraplantar injection in the ipsilateral paw to spinal nerve ligation) oxytocin administration on pain-like behavior in several nociceptive tests (tactile allodynia and thermal and mechanical hyperalgesia) on different days. ⋯ This effect was associated with a decline in the activity of primary afferent Aδ- and C-fibers. The above findings show that repeated spinal or peripheral oxytocin administration attenuates the pain-like behavior in a well-established model of neuropathic pain. This study provides a basis for addressing the therapeutic relevance of oxytocin in chronic pain conditions.
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This study describes a low-cost and time-efficient clinical sensory test (CST) battery and evaluates its concurrent validity as a screening tool to detect somatosensory dysfunction as determined using quantitative sensory testing (QST). ⋯ Quantitative sensory testing, albeit considered the gold standard to evaluate somatosensory dysfunction, requires expensive equipment, specialized examiner training and substantial time commitment which challenges its use in a clinical setting. Our study describes a CST as a low-cost and time-efficient alternative. Some of the CST tools (cold, warm, mechanical detection thresholds; pressure pain thresholds) significantly correlated with the respective QST parameters, suggesting that they may be useful in a clinical setting to detect sensory dysfunction.
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Opioids are widely prescribed for chronic pain, including neuropathic pain, despite growing evidence of long-term harm. Previous preclinical studies have documented exacerbation of nociceptive hypersensitivity, including that induced by peripheral nerve injury, by morphine. The present series of behavioral studies sought to replicate and extend our prior research, which demonstrated a multimonth exacerbation of nociceptive hypersensitivity by a 5-day course of morphine initiated 10 days after nerve injury. ⋯ Furthermore, enduring exacerbation of nociceptive hypersensitivity is also observed when the same dosing regimen for either morphine, fentanyl, or oxycodone begins 1 month after nerve injury. Finally, a striking result from these studies is that no such exacerbation of nociceptive hypersensitivity occurs when either morphine, fentanyl, or oxycodone dosing begins at the time of nerve injury. These results extend our previous findings that morphine exacerbates nociceptive hypersensitivity to the clinically relevant opioids fentanyl and oxycodone when administered after the development of nociceptive hypersensitivity, while also providing possible clinically relevant insight into when these opioids can be safely administered and not exacerbate neuropathic pain.
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Randomized Controlled Trial
A randomised, double blind, placebo-controlled crossover trial of the influence of the HCN channel blocker ivabradine in a healthy volunteer pain model: an enriched population trial.
Preclinical studies suggest that type 2 hyperpolarization-activated cyclic nucleotide gated ion channels (HCN2) are necessary for neuropathic pain. This trial assessed the influence of ivabradine, a nonselective HCN channel blocker, on capsaicin-induced hyperalgesia and pain in healthy human subjects. An enriched population comprising subjects who developed >20 cm of punctate hyperalgesia from topical capsaicin (0.5% cream applied onto 9 cm area) was identified. ⋯ However, ivabradine caused a slowing of heart rate (difference of 10.10 beats per minute [95% confidence interval -6.48 to -13.73; P-value <0.0001]). We conclude that ivabradine lacks analgesic effects in the capsaicin pain model at a dose that caused appreciable slowing of heart rate and, hence, is unlikely to prove a useful analgesic in humans. More selective drugs are required to establish a role of HCN2 for pain in humans.
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J. Pharmacol. Exp. Ther. · Nov 2019
Pharmacological Assessment of Sepiapterin Reductase Inhibition on Tactile Response in the Rat.
There is an unmet medical need for nonopioid pain therapies in human populations; several pathways are under investigation for possible therapeutic intervention. Tetrahydrobiopterin (BH4) has received attention recently as a mediator of neuropathic pain. Recent reports have implicated sepiapterin reductase (SPR) in this pain pathway as a regulator of BH4 production. ⋯ SPR inhibition and mechanical allodynia were assessed coordinately with pterin biomarkers in plasma and at the site of neuronal injury (i.e., dorsal root ganglion). Upon daily oral administration for 3 consecutive days, unbound plasma concentrations of test article exceeded the unbound in vivo rat SPR IC90 throughout the dose intervals, leading to a 60% reduction in BH4 in the dorsal root ganglion. Despite evidence for pharmacological modulation of the BH4 pathway, there was no significant effect on the tactile paw withdrawal threshold relative to vehicle-treated controls.