Department of Neurophysiology, 31235Center for Brain Research, Medical University of Vienna, Vienna, Austria.
Mol Pain. 2023 Jan-Dec;19:17448069231156657. doi: 10.1177/17448069231156657.
The aversive aspect of pain constitutes a major burden faced by pain patients. This has been recognized by the pain research community, leading to the development of novel methods focusing on affective-motivational behaviour in pain model animals. The most common tests used to assess pain aversion in animals require cognitive processes, such as associative learning, complicating the interpretation of results. To overcome this issue, studies in recent years have utilized unconditioned escape as a measure of aversion. However, the vast majority of these studies quantify jumping - a common escape behaviour in mice, but not in adult rats, thus limiting its use. Here, we present the "Heat Escape Threshold" (HET) paradigm for assessing heat aversion in rats. We demonstrate that this method can robustly and reproducibly detect the localized effects of an inflammatory pain model (intraplantar carrageenan) in male and female Sprague-Dawley rats. In males, a temperature that evoked unconditioned escape following carrageenan treatment also induced real-time place avoidance (RTPA). Systemic morphine more potently alleviated carrageenan-induced heat aversion (as measured by the HET and RTPA methods), as compared to reflexive responses to heat (as measured by the Hargreaves test), supporting previous findings. Next, we examined how blocking of excitatory transmission to the lateral parabrachial nucleus (LPBN), a key node in the ascending pain system, affects pain behaviour. Using the HET and Hargreaves tests, we show that intra-LPBN application of glutamate antagonists reverses the effects of carrageenan on both affective and reflexive pain behaviour, respectively. Finally, we employed the HET paradigm in a generalized opioid-withdrawal pain model. Withdrawal from a brief systemic administration of remifentanil resulted in a long-lasting and robust increase in heat aversion, but no change in reflexive responses to heat. Taken together, these data demonstrate the utility of the HET paradigm as a novel tool in preclinical pain research.
疼痛的厌恶性方面构成了疼痛患者面临的主要负担。这一点已被疼痛研究界所认识，导致了针对疼痛模型动物的情感动机行为的新型方法的发展。用于评估动物疼痛回避的最常见测试需要认知过程，例如联想学习，这使得结果的解释变得复杂。为了克服这个问题，近年来的研究利用非条件逃避作为回避的度量。然而，绝大多数这些研究量化了跳跃 - 一种在小鼠中常见的逃避行为，但在成年大鼠中则不然，因此限制了其使用。在这里，我们提出了用于评估大鼠热回避的“热逃避阈值”（HET）范式。我们证明，这种方法可以在雄性和雌性 Sprague-Dawley 大鼠中稳健且可重复地检测到炎症性疼痛模型（足底角叉菜胶）的局部效应。在雄性大鼠中，经角叉菜胶处理后引起非条件逃避的温度也引起实时位置回避（RTPA）。与通过 Hargreaves 测试测量的对热的反射性反应相比，全身性吗啡更有效地缓解了角叉菜胶引起的热回避（如通过 HET 和 RTPA 方法测量），这支持了先前的发现。接下来，我们研究了阻断外侧臂旁核（LPBN）的兴奋传递如何影响疼痛行为，LPBN 是上行疼痛系统中的关键节点。使用 HET 和 Hargreaves 测试，我们表明，LPBN 内应用谷氨酸拮抗剂分别逆转了角叉菜胶对情感和反射性疼痛行为的影响。最后，我们在广义阿片类药物戒断疼痛模型中使用了 HET 范式。从短暂的全身性瑞芬太尼给药中戒断导致热回避的持久而强烈的增加，但对热的反射性反应没有变化。总之，这些数据证明了 HET 范式作为临床前疼痛研究的新工具的效用。
