Substance P Enhances Excitatory Synaptic Transmission on Spinally Projecting Neurons in the Rostral Ventromedial Medulla After Inflammatory Injury

Zhang, Liang; Hammond, Donna L.

doi:10.1152/jn.91337.2008

Cited by 30 publications

(49 citation statements)

References 78 publications

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“…Using this approach, no increase in SubP content was observed on either side of the RVM four hours, four days, or two weeks after CFA treatment. This negative finding was not congruent with the results of earlier pharmacological (Pacharinsak et al, 2008; Hamity et al, 2010; Lagraize et al, 2010), electrophysiological (Budai et al, 2007; Zhang and Hammond, 2009; Brink et al, 2012) and neuroanatomical (Hamity et al, 2014) investigations whose results suggested that CFA treatment may increase SubP release. Measurements in tissue homogenates may not be able to detect small changes in content, changes that are confined to subsets of neurons or changes that occur in specific compartments such as axon terminals.…”

Section: Discussioncontrasting

confidence: 87%

Changes in the disposition of substance P in the rostral ventromedial medulla after inflammatory injury in the rat

et al. 2016

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This study examined whether peripheral inflammatory injury increases the levels or changes the disposition of substance P (SubP) in the rostral ventromedial medulla (RVM), which serves as a central relay in bulbospinal pathways of pain modulation. Enzyme immunoassay and reverse transcriptase quantitative polymerase chain reaction were used to measure SubP protein and transcript, respectively, in tissue homogenates prepared from the RVM and the periaqueductal gray and cuneiform nuclei of rats that had received an intraplantar injection of saline or complete Freund's adjuvant (CFA). Matrix Assisted Laser Desorption/Ionization Time of Flight analysis confirmed that the RVM does not contain hemokinin-1, which can confound measurements of SubP because it is recognized equally well by commercial antibodies for SubP. Levels of SubP protein in the RVM were unchanged four hours, four days and two weeks after injection of CFA. Tac1 transcripts were similarly unchanged in the RVM four days or two weeks after CFA. In contrast, the density of SubP immunoreactive processes in the RVM increased 2-fold within four hours and 2.7-fold four days after CFA injection; it was unchanged at two weeks. SubP-immunoreactive processes in the RVM include axon terminals of neurons located in the periaqueductal gray and cuneiform nucleus. Substance P content in homogenates of the periaqueductal gray and cuneiform nucleus was significantly increased four days after CFA, but not at four hours or two weeks. Tac1 transcripts in homogenates of these nuclei were unchanged four days and two weeks after CFA. These findings suggest that there is an increased mobilization of SubP within processes in the RVM shortly after injury accompanied by an increased synthesis of SubP in neurons that project to the RVM. These findings are consonant with the hypothesis that an increase in SubP release in the RVM contributes to the hyperalgesia that develops after peripheral inflammatory injury.

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Section: Discussioncontrasting

confidence: 87%

Changes in the disposition of substance P in the rostral ventromedial medulla after inflammatory injury in the rat

et al. 2016

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“…Thus, ablation of NK-1R expressing neurons in the RVM likely decreased serotonin-dependent descending facilitation. The relationship between NK-1R expressing neurons in the RVM and serotonin is unclear since there is no expression of NK-1Rs in serotonin-containing neurons (Leger et al, 2002; Zhang and Hammond, 2009; Hahm et al, 2011). Therefore, ON cells that possess NK-1Rs may excite serotonin-containing neurons in the RVM indirectly through interneurons that activate descending serotonergic neurons.…”

Section: Discussionmentioning

confidence: 99%

Loss of neurons in rostral ventromedial medulla that express neurokinin-1 receptors decreases the development of hyperalgesia

Khasabov

Simone

2013

Neuroscience

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It is well known that neurons in the rostral ventromedial medulla (RVM) are involved in descending modulation of nociceptive transmission in the spinal cord. It has been shown that activation of neurokinin-1 receptors (NK-1R) in the RVM, which are presumably located on pain facilitating ON cells, produces hyperalgesia whereas blockade of NK-1Rs attenuates hyperalgesia. To obtain a better understanding of the functions of NK-1R expressing neurons in the RVM, we selectively ablated these neurons by injecting the stable analog of substance P (SP), Sar9, Met(O2)11-Substance P, conjugated to the ribosomal toxin saporin (SSP-SAP) into the RVM. Rats received injections of SSP-SAP (1 μM) or an equal volume of 1 μM of saporin conjugated to artificial peptide (Blank-SAP). Stereological analysis of NK-1R- and NeuN-labeled neurons in the RVM was determined 21–24 days after treatment. Withdrawal responses to mechanical and heat stimuli applied to the plantar hindpaw were determined 5–28 days after treatment. Withdrawal responses were also determined before and after intraplantar injection of capsaicin (acute hyperalgesia) or complete Freund’s adjuvant (CFA) (prolonged hyperalgesia). The proportion of NK-1R-labeled neurons in the RVM was 8.8 ± 1.3% in naïve rats and 8.1 ± 0.8% in rats treated with Blank-SAP. However, injection of SSP-SAP into the RVM resulted in a 90% decrease in NK-1R-labeled neurons. SSP-SAP did not alter withdrawal responses to mechanical or heat stimuli under normal conditions, and did not alter analgesia produced by morphine administered into the RVM. In contrast, the duration of nocifensive behaviors produced by capsaicin and mechanical and heat hyperalgesia produced by capsaicin and CFA were decreased in rats pretreated with SSP-SAP as compared to those that received Blank-SAP. These data support our earlier studies using NK-1R antagonists in the RVM and demonstrate that RVM neurons that possess the NK-1R do not play a significant role in modulating acute pain or morphine analgesia, but rather are involved in pain facilitation and the development and maintenance of hyperalgesia.

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“…[84][85][86][87][88][89][90][91][92][93][94][95][96] In summary, all these neurotransmitters released by nociceptive ascending neurons over 'ON'-RVM neurons cause their hyperexcitability (Figure 4). 97 Neuropathic and inflammatory pain also causes changes in PAG neurons. Under these circumstances, the hyperexcitability of nociceptive ascending neurons not only induces sensitization of PAG neurons causing overexpression of several receptors including NMDA/AMPA and SP/NK1 but also overexpression of glutamate and brain-derived neurotrophic factor.…”

Section: Molecular Neuroplasticity Of the Descending Inhibitory Pain mentioning

confidence: 99%

Neuroplasticity of ascending and descending pathways after somatosensory system injury: reviewing knowledge to identify neuropathic pain therapeutic targets

et al. 2016

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Study design: This is a narrative review of the literature. Objectives: This review aims to be useful in identifying therapeutic targets. It focuses on the molecular and biochemical neuroplasticity changes that occur in the somatosensory system, including ascending and descending pathways, during the development of neuropathic pain. Furthermore, it highlights the latest experimental strategies, based on the changes reported in the damaged nociceptive neurons during neuropathic pain states. Setting: This study was conducted in Girona, Catalonia, Spain. Methods: A MEDLINE search was performed using the following terms: descending pain pathways; ascending pain pathways; central sensitization; molecular pain; and neuropathic pain pharmacological treatment. Results and conclusion: Neuropathic pain triggered by traumatic lesions leads to sensitization and hyperexcitability of nociceptors and projection neurons of the dorsal horn, a strengthening in the descendent excitatory pathway and an inhibition of the descending inhibitory pathway of pain. These functional events are associated with molecular plastic changes such as overexpression of voltagegated ion channels, algogen-sensitive receptors and synthesis of several neurotransmitters. Molecular studies on the plastic changes in the nociceptive somatosensory system enable the development of new pharmacological treatments against neuropathic pain, with higher specificity and effectiveness than classical drug treatments. Although research efforts have already focused on these aspects, additional research may be necessary to further explore the potential therapeutic targets in neuropathic pain involved in the neuroplasticity changes of neuropathological pathways from the injured somatosensory system.

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Substance P Enhances Excitatory Synaptic Transmission on Spinally Projecting Neurons in the Rostral Ventromedial Medulla After Inflammatory Injury

Cited by 30 publications

References 78 publications

Changes in the disposition of substance P in the rostral ventromedial medulla after inflammatory injury in the rat

Changes in the disposition of substance P in the rostral ventromedial medulla after inflammatory injury in the rat

Loss of neurons in rostral ventromedial medulla that express neurokinin-1 receptors decreases the development of hyperalgesia

Neuroplasticity of ascending and descending pathways after somatosensory system injury: reviewing knowledge to identify neuropathic pain therapeutic targets

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