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

吗啡类药物（阿片类药物）已经被使用和滥用了几个世纪，主要是因为它们具有缓解疼痛和奖励的作用。这些药物仍然是治疗疼痛的重要方法，然而，它们有多种不良的副作用，这极大地限制了它们的临床应用。这些包括镇静，抑制呼吸和奖励效应，可导致成瘾。吗啡类药物的作用原理是模仿人体内自然产生的化学物质，即内源性阿片类药物。其中最著名的是-内啡肽，它在调节我们所经历的疼痛方面起着重要作用——尤其是当我们处于压力之下时，它可以被释放出来抑制疼痛感知。-内啡肽的自然释放不会引起阿片类药物如吗啡的副作用。这可能会给我们一个线索，如何达到更好的缓解疼痛，减少副作用。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-内啡肽只在大脑中两个小的、难以接近的神经元群中产生。然而，通过使用选择性基因工程技术，我们可以将修饰受体（DREADDs）引入基因工程小鼠的-内啡肽释放神经元中。这使得我们可以通过给药来选择性地激活（或抑制）这些神经元，并研究它们对动物行为的影响。我们将测试脑干中的-内啡肽神经元是否能产生镇痛作用；评估这是否适用于慢性疼痛模型，以及这种更自然的释放阿片类药物的方式是否具有与较少副作用相关的缓解疼痛效果（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缓解是否由这些脑干-内啡肽产生神经元的激活产生。

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.