Spinal neurons that possess the substance P receptor are required for the development of central sensitization

Department of Preventive Sciences, University of Minnesota, Minneapolis, Minnesota 55455, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 11/2002; 22(20):9086-98.
Source: PubMed


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. "
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    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:
    Brain 05/2015; 138(9):2505-20. DOI:10.1093/brain/awv108 · 9.20 Impact Factor
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    • "SP is thought to play important roles in the control of myometrial contractility29 and uterine blood flow.30 SP-R, a G-protein-coupled receptor, plays a critical role in injury-induced hyperalgesia or pain.31,32 SP interacts with the SP-R to produce its postsynaptic effects.33 "
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    ABSTRACT: A copper/low-density polyethylene nanocomposite (nano-Cu/LDPE), a potential intrauterine device component material, has been developed from our research. A logical extension of our previous work, this study was conducted to investigate the expression of plasminogen activator inhibitor 1 (PAI-1), substance P (SP), and substance P receptor (SP-R) in the endometrium of Sprague Dawley rats, New Zealand White rabbits, and Macaca mulatta implanted with nano-Cu/LDPE composite. The influence of the nano-Cu/LDPE composite on the morphology of the endometrium was also investigated. Animals were randomly divided into five groups: the sham-operated control group (SO group), bulk copper group (Cu group), LDPE group, and nano-Cu/LDPE groups I and II. An expression of PAI-1, SP, and SP-R in the endometrial tissues was examined by immunohistochemistry at day 30, 60, 90, and 180 postimplantation. The significant difference for PAI-1, SP, and SP-R between the nano-Cu/LDPE groups and the SO group (P<0.05) was identified when the observation period was terminated, and the changes of nano-Cu/LDPE on these parameters were less remarkable than those of the Cu group (P<0.05). The damage to the endometrial morphology caused by the nano-Cu/LDPE composite was much less than that caused by bulk copper. The nano-Cu/LDPE composite might be a potential substitute for conventional materials for intrauterine devices in the future because of its decreased adverse effects on the endometrial microenvironment.
    International Journal of Nanomedicine 02/2014; 9(1):1127-38. DOI:10.2147/IJN.S56756 · 4.38 Impact Factor
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    • "Indeed, lesions of the RVM or pharmacological inhibition of specific pathways originating in the RVM, such as mu-opiate receptor-expressing ON neurons or serotonin–expressing neurons, results in a loss of the increased pain sensitivity seen in experimental pain models [13,14]. It has also been demonstrated electrophysiologically that lesions of the ascending lamina I pathway or pharmacological inhibition of the descending serotonergic pathway at spinal level reduces spinal nociceptive transmission in mature rats [3,15,16]. "
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    ABSTRACT: Background A small proportion of lamina I neurons of the spinal cord project upon the hindbrain and are thought to engage descending pathways that modulate the behavioural response to peripheral injury. Early postnatal development of nociception in rats is associated with exaggerated and diffuse cutaneous reflexes with a gradual refinement of responses over the first postnatal weeks related to increased participation of inhibitory networks. This study examined the postnatal development of lamina I projection neurons from postnatal day 3 (P3) until P48. Results At P3, a subset of lamina I neurons were found to express the neurokinin 1 (NK1) receptor. Using fluorogold retrograde tracing, we found that the NK1 positive neurons projected upon the parabrachial nucleus (PB) within the hindbrain. Using c-fos immunohistochemistry, we showed that lamina I and PB neurons in P3 rats responded to noxious stimulation of the periphery. Finally, ablation of lamina I neurons with substance-P saporin conjugates at P3 resulted in increased mechanical sensitivity from P45 onwards compared to control animals of the same age. Conclusions These results suggest that the lamina I pathway is present and functional at least from P3 and required for establishing and fine-tuning mechanical sensitivity in adult rats.
    Molecular Pain 04/2012; 8(1):35. DOI:10.1186/1744-8069-8-35 · 3.65 Impact Factor
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