Spinal neurons that possess the substance P receptor are required for the development of central sensitization
ABSTRACT In previous studies, we have shown that loss of spinal neurons that possess the substance P receptor (SPR) attenuated pain and hyperalgesia produced by capsaicin, inflammation, and nerve injury. To determine the role of SPR-expressing neurons in modulating pain and hyperalgesia, responses of superficial and deep lumbar spinal dorsal horn neurons evoked by mechanical and heat stimuli and by capsaicin were made after ablation of SPR-expressing neurons using the selective cytotoxin conjugate substance P-saporin (SP-SAP). Morphological analysis and electrophysiological recordings were made after intrathecal infusion of vehicle, saporin alone, or SP-SAP. SP-SAP, but not vehicle or SAP alone, produced an approximately 62% decrease in SPR-expressing neurons in the dorsal horn. Loss of SPR-expressing neurons diminished the responses of remaining neurons to intraplantar injection of capsaicin. Peak responses to 10 microg of capsaicin were approximately 65% lower in animals pretreated with SP-SAP compared with controls. Additionally, sensitization to mechanical and heat stimuli that normally follows capsaicin was rarely observed. Importantly, responses to mechanical and heat stimuli in the absence of capsaicin were not altered after SP-SAP treatment. In addition, nociceptive neurons did not exhibit windup in the SP-SAP-treated group. These results demonstrate that SPR-expressing neurons located in the dorsal horn are a pivotal component of the spinal circuits involved in triggering central sensitization and hyperalgesia. It appears that this relatively small population of neurons can regulate the physiological properties of other nociceptive neurons and drive central sensitization.
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- "LTP in lamina I neurons induced by HFS of C-fibres depends on coactivation of NMDA receptors by glutamate and neurokinin 1 receptors (NK1-R) by substance P, and resulting activation of T type calcium channels (Ikeda et al., 2003; Heinke et al., 2004; Naka et al., 2013). Substance P acting at NK1-R in the superficial dorsal horn of rats is also essential for central sensitization induced by capsaicin through activation of TRPV1-positive afferents (Nichols et al., 1999; Khasabov et al., 2002; Vierck et al., 2003; Rygh et al., 2006). Because the majority of peptidergic nerve fibres express TRPV1 across species one can assume that in our study, those neurons were eliminated by capsaicin preincubation. "
ABSTRACT: Long-term potentiation in the spinal dorsal horn requires peptidergic C-fibre activation in animals. Perceptual correlates of long-term potentiation following high-frequency electrical stimulation in humans include increased sensitivity to electrical stimuli at the high frequency stimulation site (homotopic pain-long-term potentiation) and increased sensitivity to pinprick surrounding the high frequency stimulation site (heterotopic pain-long-term potentiation, equivalent to secondary hyperalgaesia). To characterize the peripheral fibre populations involved in induction of pain-long-term potentiation, we performed two selective nerve block experiments in 30 healthy male volunteers. Functional blockade of TRPV1-positive nociceptors by high-concentration capsaicin (verified by loss of heat pain) significantly reduced pain ratings to high frequency stimulation by 47% (P < 0.001), homotopic pain-long-term potentiation by 71% (P < 0.01), heterotopic pain-long-term potentiation by 92% (P < 0.001) and the area of secondary hyperalgesia by 76% (P < 0.001). The selective blockade of A-fibre conduction by nerve compression (verified by loss of first pain to pinprick) significantly reduced pain ratings to high frequency stimulation by 37% (P < 0.01), but not homotopic pain-long-term potentiation (-5%). It had a marginal effect on heterotopic pain-long-term potentiation (-35%, P = 0.059), while the area of secondary hyperalgesia remained unchanged (-2%, P = 0.88). In conclusion, all nociceptor subclasses contribute to high frequency stimulation-induced pain (with a relative contribution of C > Aδ fibres, and an equal contribution of TRPV1-positive and TRPV1-negative fibres). TRPV1-positive C-fibres are the main inducers of both homotopic and heterotopic pain-long-term potentiation. TRPV1-positive A-fibres contribute substantially to the induction of heterotopic pain-long-term potentiation. TRPV1-negative C-fibres induce a component of homotopic self-facilitation but not heterotopic pain-long-term potentiation. TRPV1-negative A-fibres are the main afferents mediating pinprick pain and hyperalgesia, however, they do not appear to contribute to the induction of pain-long-term potentiation. These findings show that distinct peripheral fibre classes mediate induction of long-term potentiation-like pain amplification, its spatial spread to adjacent skin (i.e. secondary hyperalgesia), and the resulting enhanced sensitivity to pinprick in humans. Nociceptive afferents that induce pain amplification can be readily dissociated from those mediating pain. These findings add substantially to our understanding of the mechanisms of pain amplification, that form the basis for understanding the mechanisms of hyperalgesia encountered in patients. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: firstname.lastname@example.org.Brain 05/2015; DOI:10.1093/brain/awv108 · 10.23 Impact Factor
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- "y nociceptive signals to medullary and brainstem regions and play a critical role in controlling dorsal horn excitability through a spino - bulbo - spinal facilitatory loop ( Suzuki et al . , 2002 , Suzuki et al . , 2005 ) . Pharmacological elimination of NK1R bearing neurons prevents development of central sensitization ( Nichols et al . , 1999 , Khasabov et al . , 2002 , Suzuki et al . , 2002 , Vierck et al . , 2003 ) . In earlier work we showed that direct activation of NK1R neurons with IT SP induces a centrally - mediated hyperalgesia ( Malmberg and Yaksh , 1992 ) . In the present work , we show that after IT SP , strong pAkt , pmTOR and pS6 expression were detected in dorsal horn neurons labeled wi"
ABSTRACT: Phosphinositide 3-kinase (PI3K), Akt, and their downstream kinase, mammalian target of rapamycin (mTOR), are implicated in neural plasticity. The functional linkages of this signaling cascade in spinal dorsal horn and their role in inflammatory hyperalgesia have not been elucidated. In the present work, we identified the following characteristics of this cascade. (1) Local inflammation led to increase in rat dorsal horn phosphorylation (activation) of Akt (pAkt) and mTOR (pmTOR), as assessed by Western blotting and immunocytochemistry. (2) Increased pAkt and pmTOR were prominent in neurons in laminae I, III, and IV, whereas pmTOR and its downstream targets (pS6, p4EBP) were also observed in glial cells. (3) Intrathecal treatment with inhibitors to PI3K or Akt attenuated Formalin-induced second-phase flinching behavior, as well as carrageenan-induced thermal hyperalgesia and tactile allodynia. (4) Intrathecal rapamycin (an mTORC1 inhibitor) displayed anti-hyperalgesic effect in both inflammatory pain models. Importantly, intrathecal wortmannin at anti-hyperalgesic doses reversed the evoked increase not only in Akt but also in mTORC1 signaling (pS6/p4EBP). (5) pAkt and pmTOR are expressed in neurokinin 1 receptor-positive neurons in laminae I-III after peripheral inflammation. Intrathecal injection of Substance P activated this cascade (increased phosphorylation) and resulted in hyperalgesia, both of which effects were blocked by intrathecal wortmannin and rapamycin. Together, these findings reveal that afferent inputs trigged by peripheral inflammation initiate spinal activation of PI3K-Akt-mTOR signaling pathway, a component of which participates in neuronal circuits of facilitated pain processing.The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 02/2011; 31(6):2113-24. DOI:10.1523/JNEUROSCI.2139-10.2011 · 6.75 Impact Factor
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- "Substance P interacts with the substance P receptor, also referred to the neurokinin-1 (NK 1 ) receptor to produce its postsynaptic effects. Spinal NK 1 receptor expressing cells plays a critical role in injury-induced hyperalgesia or pain    . The physiological significant action of substance P is probably terminated by a membrane-bound protease capable of degrading substance P in the synaptic region. "
ABSTRACT: The present study sought to examine the mechanism of substance P to modulate the antinociceptive action of intrathecal (i.t.) morphine in paw-licking/biting response evoked by subcutaneous injection of capsaicin into the plantar surface of the hindpaw in mice. The i.t. injection of morphine inhibited capsaicin-induced licking/biting response in a dose-dependent manner. Substance P (25 and 50 pmol) injected i.t. alone did not alter capsaicin-induced nociception, whereas substance P at a higher dose of 100 pmol significantly reduced the capsaicin response. Western blots showed the constitutive expression of endopeptidase-24.11 in the dorsal and ventral parts of lumbar spinal cord of mice. The N-terminal fragment of substance P (1-7), which is known as a major product of substance P by endopeptidase-24.11, was more effective than substance P on capsaicin-induced nociception. Combination treatment with substance P (50 pmol) and morphine at a subthreshold dose enhanced the antinociceptive effect of morphine. The enhanced effect of the combination of substance P with morphine was reduced significantly by co-administration of phosphoramidon, an inhibitor of endopeptidase-24.11. Administration of D-isomer of substance P (1-7), [D-Pro(2), D-Phe(7)]substance P (1-7), an inhibitor of [(3)H] substance P (1-7) binding, or antisera against substance P (1-7) reversed the enhanced antinociceptive effect by co-administration of substance P and morphine. Taken together these data suggest that morphine-induced antinociception may be enhanced through substance P (1-7) formed by the enzymatic degradation of i.t. injected substance P in the spinal cord.Peptides 07/2009; 30(9):1689-96. DOI:10.1016/j.peptides.2009.06.002 · 2.61 Impact Factor