The precise site of projection of these fibers and their role in inhibition or facilitation remains unclear

The precise site of projection of these fibers and their role in inhibition or facilitation remains unclear. The amygdala in descending modulation Human imaging studies reveal connections linking the PAG to the amygdala and cortical sites (2, 31). evidence for pain modulatory mechanisms came from observations of H.K. Beecher, who noted a remarkable attenuation of pain experienced by soldiers in combat situations (1). Analogous observations have been seen in others, including athletes that continue competition despite significant injuries (see ref. 2). Beecher, a physician who served with the US Army during the Second World War, observed that as many as three-quarters of badly wounded soldiers reported no to moderate pain and did not want pain relief medication (1). This observation was striking, because the wounds were not trivial but consisted of compound fractures of long bones or penetrating wounds of the abdomen, thorax, or cranium. Moreover, only individuals who were clearly alert, responsive, and not in shock were included in his report (1), leading to the conclusion that strong emotions block pain (1). The existence of endogenous mechanisms that diminish pain through net inhibition is now generally accepted. Pain modulation likely exists in the form of a descending pain modulatory circuit with inputs that arise in multiple areas, including the Kcnj12 hypothalamus, the amygdala, and the rostral anterior cingulate cortex (rACC), feeding to the midbrain periaqueductal gray region (PAG), and with outputs from the PAG to the medulla. Neurons within the nucleus raphe magnus and nucleus reticularis gigantocellularis, which are included within the rostral ventromedial medulla (RVM), have been shown to project to the spinal or medullary dorsal horns to directly or Edotecarin indirectly enhance or diminish nociceptive traffic, changing the experience of pain (3). This descending modulatory circuit is an opioid-sensitive circuit (see below) and relevant to human experience in many settings, including in states of chronic pain, and in the actions of pain-relieving drugs, including opiates, cannabinoids, NSAIDs, and serotonin/norepinephrine reuptake blockers that mimic, in part, the actions of opiates (Figure ?(Figure1).1). While the precise mechanisms by which drugs produce pain relief is not entirely understood, strong evidence supports the actions of these drugs through the pain modulatory circuit or by mimicking the consequence of activation of this descending circuit at the level of the spinal cord. Open in a separate window Figure 1 Schematic representation of pain modularity circuitry.Nociceptive inputs enter the spinal dorsal horn Edotecarin through primary afferent fibers that synapse onto transmission neurons. The projection fibers ascend through the contralateral spinothalamic tract. Ascending projections target the thalamus, and collateral projections also target mesencephalic nuclei, including the DRt, the RVM, and the midbrain PAG. Descending projections from the DRt are a critical component of the DNIC pathway. Rostral projections from the thalamus target areas that include cortical sites and the amygdala. The lateral capsular part of the CeA (nociceptive amygdala) receives nociceptive inputs from your brainstem and spinal cord. Inputs from your thalamus and cortex enter through the lateral (LA) and basolateral Edotecarin (BLA) Edotecarin amygdala. The CeA sends outputs to cortical sites and the thalamus, in which cognitive and conscious perceptions of pain are integrated. Descending pain modulation is definitely mediated through projections to the PAG, which also receives inputs from additional sites, including the hypothalamus (data not demonstrated), and communicates with the RVM as well as other medullary nuclei that send descending projections to the spinal dorsal horn through the DLF. The noradrenergic locus coeruleus (LC) receives inputs from your PAG, communicates with the RVM, and sends descending noradrenergic inhibitory projections to the spinal cord. Antinociceptive and pronociceptive spinopetal projections from your RVM positively and negatively modulate nociceptive inputs and provide for an endogenous pain regulatory system. Ascending (reddish) and descending (green) tracts are demonstrated schematically. Areas labeled iCiv in the small diagram correspond with labeled details of the larger diagram. Top-down modulatory pathways have been shown to.