The differential role of specific POMC neuronal circuits in mediating the beneficial and detrimental effects of opioids.

特定 POMC 神经元回路在调节阿片类药物的有益和有害作用中的不同作用。

• 批准号: MR/P025749/1
• 负责人: Anthony Pickering
• 金额: $ 40.06万
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP025749%2F1
• 关键词: differential; role; specific; POMC; neuronal

Morphine-like drugs (opioids) have been used and abused for centuries, mainly for their pain-relieving and rewarding effects. These drugs still remain important treatments for pain, however, they have multiple undesirable side-effects which greatly limit their clinical usefulness. These include sedation, suppression of breathing and rewarding effects which can lead to addiction.Morphine-like drugs work by mimicking the action of chemicals made naturally in the body, called endogenous opioids. The best known of these is beta-endorphin and it has an important role in regulating the pain we experience - especially when we are under stress it can be released to suppress pain perception. This natural release of beta-endorphin does not cause the side effects that are seen with opioid drugs like morphine. This may give us a clue as to how to achieve better pain relief that has reduced side effects.A first step towards this goal is to better understand the function of the brain circuits that release endogenous opioids. This has previously been difficult as beta-endorphin is made in only two small, inaccessible groups of neurons in the brain. However, by using selective genetic engineering techniques we can introduce modified receptors (DREADDs) into the beta-endorphin releasing neurons of genetically engineered mice. This allows us to selectively activate (or inhibit) these neurons by giving an otherwise inactive drug and study the effects on animal behaviour.We will test whether the beta-endorphin neurons in the brainstem can produce an analgesic effect; assess whether this is of use in models of chronic pain and also whether this more natural way of releasing opioids exerts a pain relieving effect that is associated with fewer side effects (we believe that there may be reduced sedation, reward and addictive potential). We will also determine whether the pain relief from stress, feeding and vagal nerve stimulation are produced by the activation of these brainstem beta-endorphin producing neurons.

吗啡类药物（阿片类药物）已经使用和滥用了几个世纪，主要是因为它们具有缓解疼痛和有益的作用。这些药物仍然是治疗疼痛的重要方法，然而，它们具有多种不良副作用，极大地限制了它们的临床用途。这些包括镇静、抑制呼吸和可能导致成瘾的奖励效应。吗啡类药物的作用是模仿体内自然产生的化学物质（称为内源性阿片类药物）的作用。其中最著名的是β-内啡肽，它在调节我们所经历的疼痛方面发挥着重要作用 - 特别是当我们处于压力下时，它可以释放以抑制疼痛感知。 β-内啡肽的自然释放不会引起吗啡等阿片类药物的副作用。这可能为我们提供如何更好地缓解疼痛并减少副作用的线索。实现这一目标的第一步是更好地了解释放内源性阿片类药物的大脑回路的功能。这在以前是很困难的，因为β-内啡肽仅由大脑中两个难以接近的小神经元群产生。然而，通过使用选择性基因工程技术，我们可以将修饰受体（DREADD）引入基因工程小鼠释放β-内啡肽的神经元中。这使得我们能够通过给予一种原本无活性的药物来选择性地激活（或抑制）这些神经元，并研究其对动物行为的影响。我们将测试脑干中的β-内啡肽神经元是否可以产生镇痛作用；评估这是否适用于慢性疼痛模型，以及这种释放阿片类药物的更自然的方式是否能产生与较少副作用相关的疼痛缓解效果（我们认为可能会减少镇静、奖励和成瘾潜力）。我们还将确定压力、进食和迷走神经刺激引起的疼痛是否是通过激活这些脑干产生β-内啡肽的神经元而产生的。

项目成果

Neurons in the Dorsomedial Hypothalamus Promote, Prolong, and Deepen Torpor in the Mouse.

下丘脑背内侧的神经元促进、延长和加深小鼠的麻木状态。

• DOI: http://dx.10.1523/jneurosci.2102-21.2022
• 发表时间: 2022
• 期刊: the official journal of the Society for Neuroscience
• 作者: Ambler M

Regulation of food intake by astrocytes in the brainstem dorsal vagal complex.

脑干背侧迷走神经复合体中星形胶质细胞对食物摄入的调节。

• DOI: http://dx.10.1002/glia.23774
• 发表时间: 2020
• 期刊: Glia
• 影响因子: 6.2
• 作者: MacDonald AJ

Pro-opiomelanocortin neurons in the nucleus of the solitary tract mediate endorphinergic endogenous analgesia in mice.

孤束核中的阿片黑皮质素原神经元介导小鼠的内啡肽能内源性镇痛。

• DOI: 10.1097/j.pain.0000000000002802
• 发表时间: 2022-10-18
• 期刊: Pain
• 影响因子: 7.4
• 作者: P. H. Patra;Becks Tench;T. Hitrec;F. Holmes;R. Drake;S. Cerritelli;D. Spanswick;A. Pickering
• 通讯作者: A. Pickering

Hedonic drinking engages a supraspinal inhibition of thermal nociception in adult rats

享乐饮酒可抑制成年大鼠的热伤害感受

• DOI: http://dx.10.1097/j.pain.0000000000001482
• 发表时间: 2019
• 期刊: Pain
• 影响因子: 7.4
• 作者: Davies A

Release of beta-endorphin from brainstem POMC neurons in mice is anxiolytic but not rewarding

小鼠脑干 POMC 神经元释放 β-内啡肽具有抗焦虑作用，但无益处

• 发表时间: 2018
• 作者: Fiona Holmes