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The gate control theory of pain proposes that inhibitory neurons of the spinal dorsal horn exert critical control over the relay of nociceptive signals to higher brain areas. Here we investigated how the glycinergic subpopulation of these neurons contributes to modality-specific pain and itch processing. We generated a GlyT2::Cre transgenic mouse line suitable for virus-mediated retrograde tracing studies and for spatially precise ablation, silencing, and activation of glycinergic neurons. We found that these neurons receive sensory input mainly from myelinated primary sensory neurons and that their local toxin-mediated ablation or silencing induces localized mechanical, heat, and cold hyperalgesia; spontaneous flinching behavior; and excessive licking and biting directed toward the corresponding skin territory. Conversely, local pharmacogenetic activation of the same neurons alleviated neuropathic hyperalgesia and chloroquine- and histamine-induced itch. These results establish glycinergic neurons of the spinal dorsal horn as key elements of an inhibitory pain and itch control circuit.
Ludwig 3.0 Activation Keyl
Prior to the 1980s, most of the studies aimed at identifying brain stem neurons responsible for setting the level of SNA and ABP relied on finding neurons that responded to electrical- or pressure-induced activation of baroreceptor nerves (36, 70, 79). A limitation of this approach is that baroreceptor activation can influence physiological processes such as respiration, muscle spindle activity, and cortical activity (6, 35, 101). When searching the medullary reticular formation, including the medullary lateral tegmental field (LTF), Biscoe and Sampson (36) were unsuccessful in locating neurons with pulse-synchronous activity. Gootman et al. (62) were the first to record successfully from a few medullary neurons (exact location not stated), the activity of which was correlated to the slow waves in splanchnic SNA of a baroreceptor-intact cat. In 1981, Gebber and Barman reported the results of a comprehensive investigation of neurons in the classic pressor area of the LTF; they used time-domain analyses to identify individual neurons with naturally occurring action potentials that were synchronized to the cardiac- and respiratory-related rhythms in SNA of barbiturate-anesthetized, baroreceptor-innervated cats (10) and to the 2- to 6-Hz slow waves in SNA of baroreceptor-denervated cats (55). Two years later, Barman and Gebber (11) were the first to identify RVLM neurons with activity correlated to SNA in cats with intact or bilaterally severed baroreceptor afferents. The failure of earlier attempts (36) to locate medullary neurons with pulse-synchronous activity in anesthetized cats likely reflects the fact that most of the brain stem neurons with sympathetic nerve-related activity do not fire in every cardiac cycle, requiring computer-aided approaches to detect this periodicity.
The classic approach of assessing how a neuron responds to baroreceptor activation (36, 38, 39, 70, 79) can be used in conjunction with time- and frequency-domain analyses to determine if a neuron is part of a sympathoexcitatory or sympathoinhibitory pathway. For this purpose, the firing rates of medullary neurons with cardiac-related activity were compared at baseline and during activation of the arterial baroreceptors (e.g., by a rapid rise in ABP produced by a brief partial obstruction of the abdominal aorta with inflation of a balloon-tipped Fogarty embolectomy catheter). Baroreceptor reflex activation can reduce SNA by inhibiting central sympathetic neurons that lead to activation of SNA or by activating central sympathetic neurons that function to suppress SNA. The firing rate of most of the LTF neurons with cardiac-related activity is reduced in parallel to SNA during a rise in ABP; thus these neurons are classified as sympathoexcitatory neurons; a smaller group of LTF neurons were classified as sympathoinhibitory neurons, because their firing rate was increased during activation of the baroreceptor reflex (13, 14, 56). These findings corroborate work showing that chemical activation (glutamate microinjection) of this area leads to either increases or decreases in ABP (50, 61, 83). Moreover, chemical inactivation (muscimol microinjection) or blockade of N-methyl-d-aspartate (NMDA) excitatory amino acid receptors in this region leads to significant reductions in ABP and SNA (23, 96), verifying its primary role as a sympathoexcitatory region. As reviewed by Dampney (46) and Guyenet (65, 66), the RVLM is known to be a major source of excitatory input to sympathetic preganglionic neurons in the intermediolateral nucleus (IML) of the thoracolumbar spinal cord. Chemical activation of the RVLM leads to an increase in ABP (47, 88, 103, 105). As expected, most of the RVLM neurons with activity correlated to SNA were identified as serving a sympathoexcitatory function, because their firing rate was suppressed during activation of the baroreceptor reflex (13, 17). Moreover, blockade of excitatory amino acid receptors in the RVLM leads to a significant decrease in SNA and ABP (23, 29).
Figure 4A shows an example of antidromic activation of a CMR neuron with activity correlated to both the cardiac-related and 10-Hz rhythms in SNA. Antidromic activation was indicated by a constant-onset latency of activation in response to single shocks applied to the dorsolateral funiculus of the first thoracic spinal segment and collision of a stimulus-induced action potential with a naturally occurring action potential (77). In support of their hypothesis, Barman and Gebber (17, 18) showed that virtually all RVLM, CMR, and CVLP neurons with activity synchronized to both sympathetic rhythms projected to the thoracic spinal cord. On the other hand, none of the RDLP neurons with activity correlated to both the cardiac-related and 10-Hz rhythms were antidromically activated by thoracic spinal cord stimulation (22). This might mean that the RDLP is the site of convergence of the two sympathetic rhythm generators or that these RDLP neurons receive input from the CMR, CVLP, or RVLM. There is anatomical evidence for the latter (46, 49).
As shown in Table 1, chemical inactivation (muscimol microinjection) of any one of the areas surveyed (CMR, CVLP, LTF, RDLP, or RVLM) in baroreceptor-denervated cats causes a significant decrease in the power in the 10-Hz band of SNA that is accompanied by a marked reduction in mean ABP (16, 22, 25, 27, 29, 115). This was even the case for the LTF, which does not contain neurons with activity synchronized to the 10-Hz sympathetic rhythm, implying that the LTF plays a permissive, but not a direct, role in the genesis of the 10-Hz rhythm (16). A significant reduction in mean ABP often occurred, even if the total power in SNA was unchanged, suggesting that the 10-Hz rhythm contributed to setting the resting level of ABP before chemical inactivation of the brain stem.
My colleagues and I have also used the responses to microinjection of excitatory or inhibitory amino acid receptors into select brain stem regions to assess their role in mediating various reflex-induced changes in SNA. As shown in Fig. 6, these studies determined that NMDA receptors in the LTF play a prominent role in mediating the baroreceptor reflex in terms of both synchronizing SNA to the cardiac cycle and mediating the inhibition of SNA during a pressor response (93). This was later confirmed at the level of single neurons in the LTF by elimination of their cardiac-related activity by the iontophoresis of an NMDA receptor antagonist onto their cell bodies (28). In contrast to the well-documented role of the CVLM in mediating the baroreceptor reflex in rodents (104, 105, 108), blockade of neither NMDA nor non-NMDA receptors in a wide region of the CVLM (both rostral and caudal to the obex) disrupted the reflex; in fact, blockade of non-NMDA receptors enhanced the cardiac-related power in SNA (93). Microinjection of muscimol into the LTF showed that this region plays a critical role in mediating the effects of vagal lung inflation afferents on SNA as well as the cardiovascular, but not respiratory, effects of the Bezold-Jarisch reflex (29, 98). Microinjection of either muscimol or a non-NMDA receptor antagonist into the LTF also eliminates the sympathoexcitatory response to activation of arterial chemoreceptors, but not the sympathoexcitatory effects of electrical stimulation of vagal, trigeminal, or sciatic afferents (96). Blockade of non-NMDA receptors in the RVLM markedly attenuates the sympathoexcitatory responses induced by electrical stimulation of visceral afferent fibers in either the inferior cardiac or splanchnic nerve (26). Neither blockade of excitatory amino acid receptors nor chemical inactivation of the CVLM, LTF, or nucleus of the solitary tract alters these sympathosympathetic reflexes.
SYK and downstream kinases are essential to drive inflammation and blistering in experimental epidermolysis bullosa acquisita (EBA). This schematic summarizes the current understanding of the events leading to blistering in experimental EBA. (1) The initial event is the binding of the IgG and/or IgA autoantibodies directed against type VII collagen (COL7). (2) Thereafter, anaphylatoxins are generated by activation of the complement cascade. Furthermore, several cytokines lipid mediators are released, which collectedly leads (3) to the activation of endothelial cells and allows the (4) CD18/ICAM-1-dependent extravasation of Gr-1+ myeloid cells into the skin. (5) Within the skin, myeloid cells bind to the skin-bound immune complexes via specific activating Fc gamma receptors (FcγR). (6) FcγR binding triggers an intracellular signaling cascade involving SYK, p38, ERK, and Akt, ultimately leading to the activation of the NCF1 gene, which is part of the NADPH oxidase complex and generates reactive oxygen species (ROS). Within this pathway, we show an absolute requirement of SYK for blister induction in EBA. Blockade of downstream kinases (i.e., p38, Akt, or individual Src family kinases) only partially reduces the blistering phenotype, indicating that SYK activation is in the center stage of EBA pathogenesis. (7) Ultimately, this intracellular signaling process leads to the release of ROS and proteases from the myeloid cells, which (8) mediates blistering. Image modified from Ludwig et al. (2). 2ff7e9595c
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