Mitchell Kendall, Lebovitz Evan E, Keller Jason M, Mannes Andrew J, Nemenov Michael I, Iadarola Michael J
Department of Perioperative Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA Department of Anesthesia, Stanford University, Palo Alto, CA, USA Lasmed LLC, Mountain View, CA, USA Neurobiology and Pain Therapeutics Section, Laboratory of Sensory Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
Pain. 2014 Apr;155(4):733-745. doi: 10.1016/j.pain.2014.01.007. Epub 2014 Jan 13.
TRPV1 is expressed in a subpopulation of myelinated Aδ and unmyelinated C-fibers. TRPV1+ fibers are essential for the transmission of nociceptive thermal stimuli and for the establishment and maintenance of inflammatory hyperalgesia. We have previously shown that high-power, short-duration pulses from an infrared diode laser are capable of predominantly activating cutaneous TRPV1+ Aδ-fibers. Here we show that stimulating either subtype of TRPV1+ fiber in the paw during carrageenan-induced inflammation or following hind-paw incision elicits pronounced hyperalgesic responses, including prolonged paw guarding. The ultrapotent TRPV1 agonist resiniferatoxin (RTX) dose-dependently deactivates TRPV1+ fibers and blocks thermal nociceptive responses in baseline or inflamed conditions. Injecting sufficient doses of RTX peripherally renders animals unresponsive to laser stimulation even at the point of acute thermal skin damage. In contrast, Trpv1-/- mice, which are generally unresponsive to noxious thermal stimuli at lower power settings, exhibit withdrawal responses and inflammation-induced sensitization using high-power, short duration Aδ stimuli. In rats, systemic morphine suppresses paw withdrawal, inflammatory guarding, and hyperalgesia in a dose-dependent fashion using the same Aδ stimuli. The qualitative intensity of Aδ responses, the leftward shift of the stimulus-response curve, the increased guarding behaviors during carrageenan inflammation or after incision, and the reduction of Aδ responses with morphine suggest multiple roles for TRPV1+ Aδ fibers in nociceptive processes and their modulation of pathological pain conditions.
瞬时受体电位香草酸亚型1（TRPV1）在有髓鞘的Aδ纤维和无髓鞘的C纤维亚群中表达。TRPV1+纤维对于伤害性热刺激的传递以及炎症性痛觉过敏的建立和维持至关重要。我们之前已经表明，红外二极管激光器发出的高功率、短持续时间脉冲能够主要激活皮肤TRPV1+ Aδ纤维。在此我们表明，在角叉菜胶诱导的炎症期间或后爪切开后刺激爪中的任何一种TRPV1+纤维亚型都会引发明显的痛觉过敏反应，包括长时间的爪保护行为。超强力TRPV1激动剂树脂毒素（RTX）呈剂量依赖性地使TRPV1+纤维失活，并在基线或炎症状态下阻断热伤害性反应。外周注射足够剂量的RTX会使动物即使在急性热皮肤损伤时也对激光刺激无反应。相比之下，Trpv1-/-小鼠通常在较低功率设置下对有害热刺激无反应，但使用高功率、短持续时间的Aδ刺激时会表现出退缩反应和炎症诱导的敏化。在大鼠中，全身性吗啡使用相同的Aδ刺激以剂量依赖性方式抑制爪退缩、炎症性保护行为和痛觉过敏。Aδ反应的定性强度、刺激 - 反应曲线的左移、角叉菜胶炎症期间或切开后增加的保护行为以及吗啡对Aδ反应的减弱表明TRPV1+ Aδ纤维在伤害性过程及其对病理性疼痛状态的调节中具有多种作用。
