Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.
IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.
Eur J Pain. 2019 Apr;23(4):784-799. doi: 10.1002/ejp.1347. Epub 2019 Jan 9.
Amylin is a calcitonin gene-related peptide family member expressed by nociceptors. Amylin's expression is down-regulated following nerve damage, and studies suggested it affects nociception. We aimed at clarifying amylin's effects on chronic neuropathic pain and investigating its site of action.
Chronic neuropathic pain was induced in rats by spared nerve injury (SNI) surgery. Mechanical allodynia/hyperalgesia and cold allodynia/hyperalgesia were assessed by the von Frey, pinprick, acetone and cold plate behavioural tests, respectively. Amylin, amylin-receptor antagonist (AC187) or vehicle solutions were delivered chronically, by a subcutaneous (SC) mini-osmotic pump, or acutely, by SC or intrathecal (IT) injections. Cellular and fibre markers were used to detect spinal cord alterations in SNI rats after chronic amylin administration.
Continuous subcutaneous amylin administration aggravated cold allodynia in SNI animals, possibly via amylin-receptors (AmyR) in supraspinal areas. Acute intrathecal administration of amylin attenuated mechanical hyperalgesia, whereas AC187 reduced mechanical allodynia, suggesting distinct roles of endogenous amylin and of pharmacological amylin doses when targeting spinal cord amylin receptors. Chronic amylin administration promoted c-Fos activation only in the dorsal horn neurons of SHAM animals, suggesting a distinctive role of amylin in the activation of the spinal neuronal circuitry under neuropathic and physiological conditions. ERK1/2 phosphorylation increased in the dorsal horn neurons of SNI rats chronically treated with amylin. This ERK1/2 cascade activation may be related to amylin's effect on the aggravation of cold allodynia in SNI rats.
Amylin's nociceptive effects seem to depend on the treatment duration and route of administration by acting at different levels of the nervous system.
Amylin modulated neuropathic pain by acting at different levels of the nervous system. Whereas supraspinal areas may be involved in amylin's induced pronociception, modulation of spinal cord amylin receptors by endogenous or pharmacological amylin doses triggers both pro- and antinociceptive effects.
胰淀素是一种降钙素基因相关肽家族成员，由伤害感受器表达。神经损伤后，胰淀素的表达下调，研究表明它会影响伤害感受。我们旨在阐明胰淀素对慢性神经性疼痛的影响，并研究其作用部位。
通过 spared nerve injury（SNI）手术在大鼠中诱导慢性神经性疼痛。通过 von Frey、针刺痛、丙酮和冷板行为测试分别评估机械性痛觉过敏/痛觉过度和冷感觉过敏/痛觉过度。通过皮下（SC）迷你渗透泵，或通过 SC 或鞘内（IT）注射，慢性给予胰淀素、胰淀素受体拮抗剂（AC187）或载体溶液。在慢性胰淀素给药后，使用细胞和纤维标志物检测 SNI 大鼠脊髓的变化。
连续皮下给予胰淀素加重 SNI 动物的冷感觉过敏，可能通过脊髓以上区域的胰淀素受体（AmyR）。急性鞘内给予胰淀素可减轻机械性痛觉过敏，而 AC187 则降低机械性痛觉过敏，表明内源性胰淀素和靶向脊髓胰淀素受体的药理学胰淀素剂量具有不同的作用。慢性给予胰淀素仅在假手术动物的背角神经元中促进 c-Fos 激活，表明在神经病理性和生理条件下，胰淀素在激活脊髓神经元回路中具有独特的作用。慢性给予胰淀素可增加 SNI 大鼠背角神经元中 ERK1/2 的磷酸化。这种 ERK1/2 级联激活可能与胰淀素加重 SNI 大鼠冷感觉过敏的作用有关。
胰淀素的伤害感受效应似乎取决于治疗持续时间和给药途径，作用于神经系统的不同水平。
胰淀素通过作用于神经系统的不同水平来调节神经性疼痛。虽然中枢神经系统可能参与了胰淀素诱导的伤害感受，但内源性或药理学胰淀素剂量对脊髓胰淀素受体的调节既触发了伤害感受又触发了抗伤害感受作用。
