Forebrain Modulation of Pain

描述(申请人提供)：前脑结构如何改变脊髓后角的疼痛，以及这种调制是否受到诸如受试者的性别或疼痛类型(伤害性与神经性)等条件的影响，目前知之甚少。在雌性大鼠的热伤害性感觉模型中，我们已经证明刺激外侧下丘脑在脊髓背角产生反向调制，其中α2-肾上腺素能受体介导抗伤害感受，而α1-肾上腺素能受体介导相反的、并发的原伤害性感受。抗伤害性感受器占主导地位，但被致痛性感受器效应减弱。我们的实验数据显示，在热伤害性模型(n=6)中，刺激Lh也能在雄性大鼠(n=6)和神经病理性疼痛模型(慢性缩窄性损伤模型，简称CCI)中产生抗伤害性感觉。因此，这个相互竞争的延续方案的目的是将我们的发现扩展到CCI模型，并通过刺激Lh来检验热伤害感和CCI模型中的性别差异。 脊髓背角α-肾上腺素能受体介导的对抗性反应。在两个实验中，分别用不同剂量的卡巴胆碱(125、250、500nmol加62nmol对照)和鞘内注射α-肾上腺素能受体拮抗剂(IT)刺激黄体生成素。然后，我们将通过甩尾(TFL)和足部撤退潜伏期(FWL)来检测性别和疼痛模型对阿尔法介导的对立反应机制的影响。在所有实验中，我们将采集血液样本来测量血清雌激素和孕酮，以确定实验时女性的荷尔蒙环境。利用多元统计分析，我们将确定在热伤害性和CCI模型中，三种不同剂量的卡巴胆碱刺激的促黄体生成素在α-肾上腺素受体亚型介导的伤害性调制中是否产生不同的反应，以及女性和男性的反应是否不同。这项研究的好处来自于了解内源性镇痛所涉及的神经机制，这可以导致开发出更有效的临床治疗方法，减轻女性和男性的疼痛并促进镇痛。公共健康相关性：这项拟议的研究将研究一个大脑结构(外侧下丘脑)如何阻止雄性和雌性大鼠识别两种形式的疼痛。这两种形式的疼痛是组织损伤引起的急性疼痛和神经损伤引起的神经病理性疼痛。我们假设，雌性大鼠对这两种疼痛的识别能力会比雄性大鼠更大。

DESCRIPTION (provided by applicant): Little is known about how forebrain structures modify pain in the spinal cord dorsal horn, and whether such modulation is influenced by conditions such as sex of the subject, or the type of pain (nociceptive versus neuropathic). Using female rats, we have shown that stimulating the lateral hypothalamus (LH) in a thermal nociception model produces opposing modulation in the spinal cord dorsal horn, whereby alpha2- adrenoceptors mediate antinociception, while alpha1-adrenoceptors mediate opposing, concurrent pronociception. Antinociception predominates, but is attenuated by the pronociceptive effect. Our pilot data show that LH stimulation also produces antinociception in male rats in the thermal nociceptive model (n = 6) and in both males (n = 6) and females (n = 11) in a model of neuropathic pain (the chronic constriction injury model, or CCI). Therefore, the aim of this competing continuation proposal is to extend our findings to the CCI model and to examine sex differences in both the thermal nociception and CCI models via LH stimulation of the alpha-adrenoceptor-mediated opposing response in the spinal cord dorsal horn. In two experiments, the LH will be stimulated with carbachol in different doses (125, 250, and 500 nmol plus 62 nmol control) alone and with intrathecal injection (IT) of alpha-adrenoceptor antagonists. We will then examine the effect of sex and pain model on the mechanisms of the alpha-mediated opposing response as measured by the tail flick (TFL) and foot withdrawal latency (FWL). In all experiments, we will take blood samples to measure serum estrogen and progesterone to establish the hormonal milieu of females at the time of the experiment. Using multivariate statistical analysis, we will determine whether LH stimulation at three different carbachol doses produces different responses in alpha-adrenoceptor subtype-mediated nociceptive modulation in the thermal nociceptive and CCI models, and whether female responses differ from males. The benefits of this study come from understanding the neural mechanisms involved in endogenous analgesia that can lead to the development of more effective clinical treatments that reduce pain and promote analgesia for females as well as males. PUBLIC HEALT RELEVANCE: The proposed study will examine how one brain structure (lateral hypothalamus) prevents recognition of two forms of pain in male and female rats. The two forms of pain are acute pain caused by tissue injury and neuropathic pain from damage to nerves. We hypothesize that the lateral hypothalamus will decrease the recognition of both types of pain in female rats more than male rats.