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

脊髓上疼痛控制中心的生理学：它们的出生后成熟和在损伤中的作用引起感觉处理的长期改变

• 批准号: BB/I001565/1
• 负责人: Gareth Hathway
• 金额: $ 42.73万
• 依托单位: University of Nottingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2011
• 资助国家: 英国
• 起止时间: 2011 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FI001565%2F1
• 关键词: physiology; supraspinal; pain; control; centres

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.

年轻的动物和人类对疼痛的反应与成年人不同。他们的痛阈较低，对疼痛的反应夸张和不协调，对镇痛药物的敏感性不同。值得注意的是，生命早期的疼痛可以改变一个人成熟后对进一步疼痛的反应方式。在生命早期暴露于疼痛的动物和人类在成熟后显示出改变的感觉处理，并且对随后的再损伤有夸大的反应。因此，生命早期的疼痛有可能显着影响个人的福利在其整个余生。对这些差异的一种解释是，在年幼动物的脊髓内，神经系统处理疼痛信息的第一部分，缺乏抑制性神经传递。越来越多的人认识到，脊髓上中心在疼痛处理中发挥着核心作用，但有趣的是，这些网站对新生儿伤害感受的贡献在很大程度上被忽视了。相反，该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主要脊髓上来源是脑干中的专门区域。在健康成人的活动中，这些区域之一，头端腹侧延髓（RVM）通过下行脊髓神经束传递到背角，在那里它们抑制脊髓兴奋性。然而，在慢性疼痛状态下，RVM通过释放刺激脊髓神经元的神经递质来增加疼痛。最近我已经证明，在年轻大鼠中，这些双向通路不存在，RVM只能兴奋脊髓。我已经证明，这些通路在青春期前后成熟并变得像成年人一样。这些研究已经证明了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内发生的过程，使其在年轻动物中表现不同，我们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，以了解动物成熟时RVM中神经元的基本生理特性的变化。使用电生理技术，我将比较如何个别RVM神经元对疼痛刺激在麻醉大鼠的不同出生后年龄（7，21和40（成人）天），演示如何神经元组成的RVM的变化，作为动物的成熟。我将研究RVM中发生的影响综合疼痛行为大小的过程，并观察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），并在电或化学操纵RVM的同时测量综合反射行为的幅度。至关重要的是，我将研究RVM在感觉处理的长期改变中起什么作用，这是早期生活疼痛的结果，通过诱导出生后的单侧后爪炎症，并研究RVM生理学和成年后的综合疼痛反应。我有初步的数据，证明了RVM在感觉加工的长期变化中发挥的关键作用。这个项目很重要，因为它将提高我们对疼痛通路如何形成的理解，它们在年轻动物中的行为如何不同，RVM在早期生活疼痛中的重要性，以及不成熟的疼痛如何导致整个生命中疼痛反应的改变，这有可能影响早期生活中疼痛的临床和兽医治疗。

项目成果

Cancer Chemotherapy in Early Life Significantly Alters the Maturation of Pain Processing.

• DOI: 10.1016/j.neuroscience.2017.11.032
• 发表时间: 2018-09-01
• 期刊: Neuroscience
• 影响因子: 3.3
• 作者: Hathway GJ;Murphy E;Lloyd J;Greenspon C;Hulse RP
• 通讯作者: Hulse RP

The emergence of adolescent onset pain hypersensitivity following neonatal nerve injury.

• DOI: 10.1186/1744-8069-8-30
• 发表时间: 2012-04-24
• 期刊: Molecular pain
• 影响因子: 3.3
• 作者: Vega-Avelaira D;McKelvey R;Hathway G;Fitzgerald M
• 通讯作者: Fitzgerald M

Surgical injury in the neonatal rat alters the adult pattern of descending modulation from the rostroventral medulla.

• DOI: 10.1097/aln.0000000000000658
• 发表时间: 2015-06
• 期刊: Anesthesiology
• 影响因子: 8.8
• 作者: Walker SM;Fitzgerald M;Hathway GJ
• 通讯作者: Hathway GJ

Age-dependent plasticity in endocannabinoid modulation of pain processing through postnatal development.

• DOI: 10.1097/j.pain.0000000000001027
• 发表时间: 2017-11
• 期刊: Pain
• 影响因子: 7.4
• 作者: Kwok CH;Devonshire IM;Imraish A;Greenspon CM;Lockwood S;Fielden C;Cooper A;Woodhams S;Sarmad S;Ortori CA;Barrett DA;Kendall D;Bennett AJ;Chapman V;Hathway GJ
• 通讯作者: Hathway GJ