Posterior hypothalamic modulation of pain

描述（由申请人提供）：下丘脑后部（PH）是一个未被充分研究但潜在强大的部位，可激活调节疼痛的下行脑干系统。关于前脑结构如何改变脊髓背角的急性痛觉性或慢性神经性疼痛，以及这种调节是否受到性别和疼痛类型等条件的影响，我们知之甚少。利用雌性成年大鼠，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节；2) α 2-肾上腺素受体介导的抗感觉；3) α -肾上腺素受体介导的对立并发前觉。抗感觉作用占主导地位，但被前感觉作用减弱。我们发表的数据显示，在神经性疼痛模型（慢性收缩损伤模型，CCI）中，PH刺激对雌性（n = 11）大鼠也产生了强大的抗痛觉作用，而在CCI雄性（n = 3）大鼠中，初步数据显示PH诱导的抗痛觉作用。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，也不知道α -肾上腺素受体是否会以相同的方式基于动物性别或疼痛类型发挥作用。脑深部电刺激在临床上用于治疗严重头痛，效果良好，副作用少，但尚未用于治疗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发现的PH刺激对疼痛的潜在缓解作用，PH可能是对人类全身性疼痛进行深部脑刺激的有效部位。因此，本研究的目的是扩展我们的研究结果，以研究PH刺激剂（甲萘酚）的剂量、性别和疼痛类型（伤害性或神经性）对脊髓背角α -肾上腺素受体介导的对立反应的激活的影响。在两项实验中，PH将被单独使用四种剂量（62、12、250、500 nmol）的恰巴醇和鞘内注射（IT）的α -肾上腺素能受体拮抗剂刺激。然后，我们将研究性别、疼痛类型和剂量对通过足部戒断潜伏期（FWL）测量的α介导的对立反应机制的影响。在所有实验中，我们将抽取雌性Sprague-Dawley大鼠的血液样本，测量血清雌二醇和黄体酮，以建立实验时的激素环境。通过多变量统计分析，我们将确定PH刺激是否会在α -肾上腺素能受体亚型介导的伤害性调节和CCI模型中产生不同的反应，女性的反应是否与男性不同，以及PH刺激剂的剂量是否会影响结果。研究结果将对开发更有效的个体化临床治疗方法产生影响，以减少女性和男性成人的神经性疼痛并促进镇痛。由于这种潜在的治疗方法已经用于神经血管性头痛，我们在整个动物身上的应用为细胞机制和人类丛集性头痛的研究提供了一个关键的翻译，这些丛集性头痛可能有不同的疼痛机制，而不是发生在身体其他部位的疼痛。

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.