Posterior hypothalamic modulation of pain

描述(申请人提供)：下丘脑后部(PH)是一个未被充分研究但潜在的强大的激活下行脑干系统来调节疼痛的地方。关于前脑结构如何改变脊髓背角的急性伤害性或慢性神经性疼痛，以及这种调制是否受到性别和疼痛类型等条件的影响，人们知之甚少。在雌性成年大鼠的急性热痛模型中，我们证明：1)刺激PH在脊髓背角产生反向调制；2)α2-肾上腺素能受体介导抗伤害感受；3)α1-肾上腺素能受体介导相反的、并发的原伤害感受。抗伤害性感受器占主导地位，但被致痛性感受器效应减弱。我们发表的数据表明，在神经病理性疼痛模型(慢性缩窄性损伤模型，CCI)中，PH刺激也在雌性(n=11)大鼠中产生强大的抗伤害感受，而飞行员数据显示，在CCI雄性(n=3)大鼠中，PH刺激也产生了强烈的抗伤害感受。我们不知道PH刺激的程度(由PH刺激的剂量决定)是否会影响性别或疼痛类型的结果，或者α-肾上腺素能受体的作用方式是否与动物性别或疼痛类型相同。PH中的脑深部刺激在临床上用于治疗严重的头痛，取得了成功，副作用很小，但尚未用于其他类型的神经性疼痛。考虑到神经病理性疼痛问题的严重性，以及PH刺激在人类和大鼠中显示的潜在疼痛缓解，PH可能是治疗全身性疼痛的人类脑深部刺激的有效部位。因此，这项建议的目的是扩大我们的发现，以检查PH刺激剂(卡巴胆碱)的剂量、性别和疼痛类型(伤害性或神经病理性)在激活脊髓背角α-肾上腺素受体介导的相反反应中的作用。在两个实验中，仅用四种剂量的卡巴胆碱(62，12,250,500nmol)和鞘内注射α-肾上腺素能受体拮抗剂(IT)刺激PH。然后，我们将研究性别、疼痛类型和剂量对阿尔法介导的相反反应机制的影响，这是通过足部撤退潜伏期(FWL)来衡量的。在所有实验中，我们将从雌性Spraogue-Dawley大鼠身上采集血液样本，以测定血清雌二醇和孕酮，以确定实验时的激素环境。利用多元统计分析，我们将确定在伤害性反应和CCI模型中，PH刺激在α-肾上腺素受体亚型介导的伤害性感受调制中是否产生不同的反应，女性和男性的反应是否不同，以及PH刺激剂的剂量是否影响结果。结果将对开发更有效的个体化临床治疗产生影响，这些治疗可以减少女性和男性成年人的神经病理性疼痛并促进止痛。由于潜在的治疗方法已经用于神经血管头痛，我们在整个动物身上所做的应用在细胞机制和对人类丛集性头痛所做的工作之间提供了一个关键的转换部分，人类丛集性头痛可能具有不同于身体其他部位疼痛的疼痛机制。

DESCRIPTION (provided by applicant): The posterior hypothalamus (PH) is an understudied but potentially powerful site for activating descending brainstem systems that modulate pain. Little is known about how forebrain structures modify either acute nociceptive or chronic neuropathic pain in the spinal cord dorsal horn, and whether such modulation is influenced by conditions such as sex and pain type. Using female adult rats, we demonstrated in an acute thermal pain model that: 1) stimulating the PH produced opposing modulation in the spinal cord dorsal horn; 2) alpha2-adrenoceptors mediated antinociception; and 3) alpha1-adrenoceptors mediated opposing, concurrent pronociception. Antinociception predominates, but is attenuated by the pronociceptive effect. Our published data show that PH stimulation also produces robust antinociception in female (n = 11) rats in a model of neuropathic pain (the chronic constriction injury model, or CCI), and pilot data demonstrated PH-induced antinociception in male (n = 3) rats with CCI. We do not know whether the extent of PH stimulation (as determined by dose of PH stimulation) affects outcomes in either sex or pain type, or whether alpha- adrenoceptors function the same way based on animal sex or pain type. Deep brain stimulation in the PH is used clinically for severe headaches with success and with few side effects, but has not been used for other types of neuropathic pain. Given the magnitude of the problem of neuropathic pain and the potential pain relief from PH stimulation demonstrated in humans and rats, the PH may be an effective site for deep brain stimulation in humans for systemic types of pain. Therefore, the aim of this proposal is to extend our findings to examine dose of PH stimulating agent (carbachol), sex, and pain type (nociceptive or neuropathic) in activation of the alpha-adrenoceptor-mediated opposing response in the spinal cord dorsal horn. In two experiments, the PH will be stimulated with four doses of carbachol (62, 12, 250, 500 nmol) alone and with intrathecal injection (IT) of alpha-adrenoceptor antagonists. We will then examine the effect of sex, pain type and dose on the mechanisms of the alpha-mediated opposing response as measured by foot withdrawal latency (FWL). In all experiments, we will take blood samples from female Sprague-Dawley rats to measure serum estradiol and progesterone to establish the hormonal milieu at the time of the experiment. Using multivariate statistical analysis, we will determine whether PH stimulation produces different responses in alpha-adrenoceptor subtype-mediated nociceptive modulation in the nociceptive and CCI model, whether female responses differ from males, and whether the dose of the PH stimulating agent affects the outcome. Results will have an impact on the development of more effective individualized clinical treatments that reduce neuropathic pain and promote analgesia in female and male adults. Because the potential treatment has already been used for neurovascular headaches, our application done in whole animals provides a critical translational piece between cellular mechanisms and work done with human cluster headaches that may have different pain mechanisms than pain occurring elsewhere in the body.