Forebrain Modulation of Pain

描述（由申请人提供）：关于前脑结构如何改变脊髓背角的疼痛，以及这种调节是否受到诸如受试者性别或疼痛类型（伤害性与神经性）等条件的影响，知之甚少。使用雌性大鼠，我们已经表明，刺激外侧下丘脑（LH）在热伤害性感受模型中产生相反的调制脊髓背角，从而α 2-肾上腺素受体介导抗伤害性感受，而α 1-肾上腺素受体介导相反的，同时pronociception。抗伤害感受占主导地位，但被原伤害感受效应减弱。我们的试验数据表明，LH刺激也产生抗伤害性感受的雄性大鼠在热伤害性模型（n = 6）和在男性（n = 6）和女性（n = 11）在神经性疼痛模型（慢性压迫性损伤模型，或CCI）。因此，这一竞争性延续建议的目的是将我们的研究结果扩展到CCI模型，并通过LH刺激来检查热伤害感受和CCI模型中的性别差异。 脊髓背角中α-肾上腺素受体介导的对抗反应。在两个实验中，LH将单独用不同剂量的卡巴胆碱（125、250和500 nmol加62 nmol对照）刺激，并与鞘内注射（IT）α-肾上腺素受体拮抗剂一起刺激。然后，我们将研究性别和疼痛模型对α介导的对抗反应的机制的影响，通过甩尾（TFL）和足退缩潜伏期（FWL）来测量。在所有实验中，我们将采集血样以测量血清雌激素和孕激素，以建立实验时女性的激素环境。使用多变量统计分析，我们将确定是否LH刺激在三个不同的卡巴胆碱剂量产生不同的反应，在α-肾上腺素受体亚型介导的伤害性调制的热伤害性和CCI模型，以及女性的反应是否不同于男性。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，这可以导致开发更有效的临床治疗方法，减少疼痛，促进女性和男性的镇痛。公共卫生相关性：这项拟议中的研究将研究一种大脑结构（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。疼痛的两种形式是由组织损伤引起的急性疼痛和由神经损伤引起的神经性疼痛。我们推测，外侧下丘脑将减少识别这两种类型的疼痛在雌性大鼠比雄性大鼠。

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.