The physiology of supraspinal pain control centres: their postnatal maturation and role in injury induced long-term alterations in sensory processing

幼年动物和人类对疼痛的反应与成人不同。他们的痛阈值较低，对疼痛的反应夸大和不协调，对止痛药的敏感性不同。值得注意的是，早年的疼痛会改变一个人成熟后对进一步疼痛的反应方式。在生命早期暴露在疼痛中的动物和人类都会在成熟后表现出感觉处理的改变，并对随后的再次伤害做出夸大的反应。因此，早年的痛苦有可能在一个人的余生中极大地影响其福利。对这些差异的一种解释是，在幼年动物的脊髓内，缺乏抑制性神经传递，脊髓是神经系统处理痛苦信息的第一部分。越来越多的人认识到，脊髓上中枢在疼痛处理中发挥着核心作用，但有趣的是，这些部位对新生儿伤害性感受的贡献在很大程度上被忽视了。相反，这一领域的大多数研究都集中在脊髓背角水平的发育变化上。在成人中，脊髓中抑制性神经传递的一个主要的棘上来源是脑干中的专门区域。在健康成年人中，在这些区域活动的头端腹侧延髓(RVM)通过下行脊神经束传送到背角，在那里它们抑制脊髓的兴奋性。然而，在慢性疼痛状态下，RVM通过释放神经递质来刺激脊髓神经元，从而增加疼痛。最近我发现，在幼年大鼠身上，这种双向通路是不存在的，RVM只能兴奋脊髓。我已经证明，这些途径在青春期前后的一段时间内会成熟，变得像成年人一样。这些研究表明，RVM在控制幼年和成年动物脊髓中伤害性通路的兴奋性方面具有巨大的影响。然而，我们不了解RVM内发生的使其在幼年动物中表现不同的过程，我们也不了解这种不成熟如何影响对疼痛的长期反应。我将进行一系列实验，以了解随着动物的成熟，RVM中神经元的基本生理特性的变化。使用电生理学技术，我将比较不同出生后(7、21和40天)麻醉大鼠的RVM神经元对疼痛刺激的反应，展示组成RVM的神经元如何随着动物的成熟而变化。我将研究RVM中发生的影响综合疼痛行为大小的过程，并看看这些过程如何随着年龄的增长而变化。我将专门激活足部的疼痛检测神经元(C纤维)，并在电气或化学操作RVM的同时测量综合反射行为的大小。至关重要的是，我将通过在出生后引发单侧后掌炎症，以及研究RVM的生理学和成年后的综合疼痛反应，来研究RVM在感觉处理的长期变化中扮演的角色，这些变化是早期生活疼痛的结果。我有初步的数据表明，RVM在这些长期的感觉处理变化中扮演着关键角色。这个项目很重要，因为它将提高我们对疼痛通路如何形成，它们在幼年动物中的不同表现，RVM在早期生命疼痛中的重要性，以及未成熟疼痛如何导致整个生命过程中疼痛反应改变的理解，这可能会影响早期疼痛的临床和兽医治疗。

Young animals and humans respond to pain differently than adults. Their pain thresholds are lower, their responses to pain are exaggerated and uncoordinated and their sensitivities to analgesic drugs are different. Significantly, pain in early life can alter the way an individual responds to further pain after they mature. Both animals and humans exposed to pain in early life display altered sensory processing following maturation and have exaggerated responses to subsequent re-injury. Early life pain therefore has the potential to significantly affect the welfare of an individual throughout the rest of its life. One explanation for these differences is that within the spinal cord of young animals, the first part of the nervous system to process painful information, there is a lack of inhibitory neurotransmission. It is increasingly being recognised that supraspinal centres play a central role in pain processing, yet interestingly the contribution of these sites to neonatal nociception has been largely ignored. Instead the majority of research in this area has focussed upon developmental changes at the level of the dorsal horn of the spinal cord. In adults a major supraspinal source of inhibitory neurotransmission in the spinal cord are specialised areas in the brainstem. In healthy adults activity in one these areas, the rostral ventral medulla (RVM) is conveyed via descending spinal nerve tracts to the dorsal horn where they inhibit spinal excitability. However, in chronic pain states, the RVM increases pain by releasing neurotransmitters which excite spinal cord neurones. Recently I have shown that in young rats these bi-directional pathways do not exist, the RVM can only excite the spinal cord. I have shown that these pathways mature and become adult-like over a period around puberty. These studies have demonstrated the huge influence the RVM has in governing the excitability of nociceptive pathways in the spinal cord of young and adult animals. However we do not understand the processes taking place within the RVM that make it behave differently in young animals and we do not understand how this immaturity influences long-term responses to pain. I will perform a series of experiments that will understand the changes in the basic physiological properties of neurones in the RVM as an animal matures. Using electrophysiological techniques I will compare how individual RVM neurones respond to painful stimuli in anaesthetised rats of different postnatal ages (7, 21 and 40 (adult) days old), demonstrating how neurones which make up the RVM change as animals mature. I will study the processes that take place in the RVM that influence the magnitude of integrated pain behaviours and see how these change with increasing age. I will specifically activate pain detecting neurones (C-fibres) in the foot and measure the magnitude of integrated reflex behaviours whilst electrically or chemically manipulating the RVM. Crucially I will investigate what role the RVM plays in long-term alterations in sensory processing which are a consequence of early life pain by inducing unilateral hindpaw inflammation just after birth and studying RVM physiology and integrated pain responses in adulthood. I have preliminary data which demonstrate the key role that the RVM plays in these long-term alterations in sensory processing. This project is important because it will improve our understanding of how pain pathways form, how they behave differently in young animals, how important the RVM is in early life pain, and how pain in immaturity results in altered pain responses throughout life which has the potential to impact clinical and veterinary treatment of pain in early life.