Pain
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The ability to sense and respond to thermal stimuli at varied environmental temperatures is essential for survival in seasonal areas. In this study, we show that mice respond similarly to ramping changes in temperature from a wide range of baseline temperatures. ⋯ The adjustment of this set point requires transient receptor potential cation channel, subfamily member 8 (TRPM8), but not transient receptor potential cation channel, subfamily A, member 1 (TRPA1), and is regulated by phospholipase C (PLC) activity. Overall, our findings suggest that temperature response thresholds in mice are dynamic, and that this ability to adapt to environmental temperature seems to mirror the in vitro findings that PLC-mediated hydrolysis of phosphoinositol 4,5-bisphosphate modulates TRPM8 activity and thereby regulates the response thresholds to cold stimuli.
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Chronic pain after peripheral nerve damage is often accompanied by a reduction in prefrontal cortex (PFC)-related cognitive functions, which are regulated by noradrenaline, released from efferents originating in the locus coeruleus (LC). L5 to L6 spinal nerve ligation (SNL) in rats increased tissue content and extracellular concentrations of noradrenaline in microdialysates from the PFC, and impaired attentional level in the novel object recognition test. Systemic gabapentin, commonly used to treat chronic pain, impaired the novel object recognition task in normal but not SNL animals. ⋯ In contrast, locally perfused gabapentin reduced noradrenaline release in the PFC in vivo and in PFC synaptosomes in vitro. SNL- and gabapentin-induced impairment of novel object recognition task were reversed by intraperitoneal injection of the α1-adrenoceptor antagonist prazosin. These results suggest that increase in noradrenergic tone, induced by nerve injury or gabapentin, impairs PFC functions possibly via α1-adrenoceptor-mediated mechanisms; that the net effect of gabapentin on noradrenaline release in the PFC would depend on sometimes opposing actions at different sites; and that nerve injury selectively impairs the response to gabapentin in PFC-projecting neurons in the LC.
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Evaluation of nociceptive sensitisation in canine osteoarthritis studies has been poorly reported, or even related to other clinical symptoms. In 16 dogs, peak vertical force (PVF), subjective pain assessment using 3 scales, sympathetic stress response with electrodermal activity (EDA) measurement, and behavioural changes with video analysis and telemetered motor activity were quantified at baseline (D-7), and 28 and 56 days post transection of the cranial cruciate ligament. As markers of central sensitisation, selected spinal cord biomarkers (substance P and transthyretin) were quantified at D56. ⋯ Compared to tiludronate, at D56, vehicle-treated dogs had increased spinal substance P (P=0.01), concomitant decreased transthyretin (P=0.02), and (compared to baseline) demonstrated peripheral and central QST sensitisation, which was not present for tiludronate. Only PVF, the spontaneous behaviour "walking with full weight-bearing," and EDA were associated with occurrence of QST sensitisation and indicated significant tiludronate analgesic efficacy after inclusion of central QST sensitisation as a predictor variable in the statistical model. This study establishes the strong interest to implement QST as a predictor of canine osteoarthritis pain symptoms explained by pain sensitisation.