Posterior hypothalamic modulation of pain

描述（由申请人提供）：后下丘脑（PH）是一个未充分研究但潜在强大的激活调节疼痛的下行脑干系统的部位。关于前脑结构如何改变脊髓背角的急性伤害性疼痛或慢性神经性疼痛，以及这种调节是否受性别和疼痛类型等条件的影响，人们知之甚少。使用雌性成年大鼠，我们在急性热痛模型中证明：1）刺激PH在脊髓背角产生相反的调制; 2）α 2-肾上腺素受体介导的抗伤害感受; 3）α 1-肾上腺素受体介导的相反的、同时的原伤害感受。抗伤害感受占主导地位，但被原伤害感受效应减弱。我们发表的数据表明，PH刺激也产生强大的抗伤害性感受雌性大鼠（n = 11）在神经性疼痛模型（慢性压迫性损伤模型，或CCI），和试点数据证明PH诱导的抗伤害性感受雄性大鼠（n = 3）CCI。我们不知道PH刺激的程度（由PH刺激的剂量决定）是否影响性别或疼痛类型的结局，或者α-肾上腺素受体是否以相同的方式基于动物性别或疼痛类型发挥作用。PH中的深部脑刺激在临床上用于严重头痛，成功且副作用很少，但尚未用于其他类型的神经性疼痛。考虑到神经性疼痛问题的严重性以及在人类和大鼠中证实的PH刺激的潜在疼痛缓解，PH可能是人类深部脑刺激治疗全身性疼痛的有效部位。因此，本建议的目的是扩展我们的研究结果，检查剂量的PH刺激剂（卡巴胆碱），性别和疼痛类型（伤害性或神经性）在激活的α-肾上腺素受体介导的脊髓背角的对立反应。在两个实验中，将用单独的四个剂量的卡巴胆碱（62、12、250、500 nmol）和鞘内注射（IT）α-肾上腺素受体拮抗剂刺激PH。然后，我们将研究性别，疼痛类型和剂量对阿尔法介导的对立反应的机制的影响，通过足退缩潜伏期（FWL）测量。在所有实验中，我们将从雌性Sprague-Dawley大鼠中采集血样，以测量血清雌二醇和孕酮，从而在实验时建立激素环境。使用多变量统计分析，我们将确定PH刺激是否产生不同的反应，在α-肾上腺素受体亚型介导的伤害性调制的伤害性和CCI模型，女性的反应是否不同于男性，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，这些治疗可减少女性和男性成人的神经性疼痛并促进镇痛。由于潜在的治疗方法已经用于神经血管性头痛，我们在整个动物中的应用提供了细胞机制和人类丛集性头痛工作之间的关键转换，人类丛集性头痛可能具有与身体其他部位发生的疼痛不同的疼痛机制。

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.