Neurochemistry of Gestation-produced Analgesia

妊娠的抗伤害性感觉(GSA)及其激素模拟(HSPA)是整合的结果 具有多种成分，需要强啡肽(Dyn)/K和脑啡肽/6阿片类药物的同时活性 受体(Enk/DOR)脊髓止痛系统。HSPA期间增强脊髓Dyn的释放 伤害素对诱发的Dyn释放的抑制丧失及其DOR偶联的转化 对促进的抑制。经腹下神经的传入传入与脊髓的激活 GSA和HSPA也需要去甲肾上腺素受体(NAR)。然而，机制(S) 这些变化背后的原因尚不清楚。我们的生化和初步免疫组织化学 (IHC)的数据使我们能够制定出一个构成基础的神经元相互作用的综合模型 GSA和HSPA。我们假设DOR对Enk释放的抑制作用转变为促进作用 由静脉曲张引起的脊髓血管活性肠肽(VIP)释放增加而触发 顶端的Dyn神经元。这与Dyn表达的DORs的激活单独或结合使用 神经元，增加它们的cAMP含量。我们认为，这些事件对DOR的损失至关重要- DOR偶联抑制和DOR偶联促进Dyn释放的出现以及DOR偶联促进Dyn释放的损失 其抑制作用是通过伤害素。我们还假设，在热休克过程中，有增强的dyn释放效应。 由dyn神经元表达的脊髓a2c-Nars。提出了四个主要的具体目标 以此来验证该模型：(1)确定妊娠和HSP对脊髓VIP释放的影响。 这将通过放射免疫分析和体内VIP受体使用体外脊髓组织进行评估 由IHC可视化的内部化。(2)确定(A)VIP受体激活的影响，单独和在 联合DOR激活对对照脊髓组织释放Dyn的调节作用 (B)确定a2c-NAR激动剂和拮抗剂对获得的脊髓组织中Dyn释放的影响 来自对照和热休克动物。(3)测定活体(A)脊髓对GSA和HSPA的影响 VIP受体阻断和(B)抑制脊髓蛋白激酶A(4)决定空间关系 GSA和HSPA组分及卵巢性类固醇激素对其患病率的影响。 初级传入神经的激活预计会释放兴奋性递质， 产生痛苦，而不是改善其知觉。然而，有数据表明，初级传入 活性也可以增强阿片类药物的抗伤害性。我们提议的实验应该提供一个框架 以进一步理解这一悖论。这项拟议中的研究也应该揭示出 卵巢性类固醇改变(内脏)损伤诱导的脊髓重塑而不是产生痛觉减退 常在非妊娠状态下引起的神经病理性疼痛。

The antinociception of gestation (GSA) and its hormonal simulation (HSPA) result from the integration of multiple components and requires concomitant activity of dynorphin (Dyn)/K and enkephalin/6 opioid receptor (enk/DOR) spinal analgesic systems. Enhanced release of spinal Dyn during HSPA results from the loss of inhibition of evoked Dyn release by nociceptin and the conversion of its DOR-coupled inhibition to facilitation. Afferent input via the hypogastric nerve (HGN) and activation of spinal noradrenergic receptors (NARs) are also required for GSA and HSPA. However, the mechanism(s) underlying these changes remains unknown. Our biochemical and preliminary immunohistochemical (IHC) data have allowed us to formulate an integrated model of the neuronal interactions that underlie GSA and HSPA. We hypothesize that the shift from inhibition to facilitation of enk release by DOR is triggered by increased release of spinal vasoactive intestinal polypeptide (VIP) from varicosities that appose Dyn neurons. This, alone or in combination with activation of DORs that are expressed by Dyn neurons, augments their cAMP content. We contend that these events are critical for the loss of DOR- coupled inhibition and the appearance of DOR-coupled facilitation of Dyn release as well as for the loss of its inhibition via nociceptin. We also postulate that during HSP, there are enhanced Dyn releasing effects of the spinal a2c-NARs that are expressed by Dyn neurons. Four major specific aims are proposed with which to validate this model: (1) Determine the effect of pregnancy and HSP on the release of spinal VIP. This will be assessed using ex vivo spinal tissue via radioimmunoassay as well as via in vivo VIP receptor internalization visualized by IHC. (2) Determine (a) the effect of VIP receptor activation, alone and in combination with DOR activation, on the regulation of spinal Dyn release from control spinal tissue and (b) determine the effects of a2c-NAR agonists and antagonists on Dyn release from spinal tissue obtained from control and HSP animals. (3) Determine the consequences to GSA and HSPA of in vivo (a) spinal VIP receptor blockade and (b) inhibition of spinal protein kinase A. (4) Determine the spatial relationships among components of GSA and HSPA and the influence of ovarian sex steroids on their prevalence. Activation of primary afferents would be expected to release excitatory transmitters that should produce pain, not ameliorate its perception. However, there are data indicating that primary afferent activity can also enhance opioid antinociception. Our proposed experiments should provide a framework for further understanding this paradox. The proposed research should also shed light on the ability of ovarian sex steroids to alter (visceral) injury-induced spinal remodeling to produce hypoalgesia instead of the neuropathic pain that often results during the nonpregnant state.