Contribution of Substance P and Neurokinin A to the Differential Injury-Induced Thermal and Mechanical Responsiveness of Lamina I and V Neurons

Mazarío, Javier; Basbaum, Allan I.

doi:10.1523/jneurosci.2992-06.2007

Cited by 17 publications

(16 citation statements)

References 36 publications

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“…This is partially consistent with recent studies showing that AITC significantly enhanced murine deep dorsal horn WDR neuronal responses to only the weakest mechanical stimulus (130 mN) while having no significant effect on responses to stronger stimuli (Mazario and Basbaum 2007). However, other studies have shown significant enhancement of neuronal responses to innocuous mechanical stimuli, and expansion of receptive fields, in rats and mice after application of AITC adjacent to the mechanosensitive receptive field of spinal WDR or NS neurons (Pertovaara 1998;Weng et al 2001;Woolf and King 1990;Woolf et al 1994).…”

Section: Mechanically and Electrically Evoked Responsessupporting

confidence: 90%

“…Previous studies of WDR neurons in lamina V of mice reported significant enhancement of neuronal responses to 40°C (but not 45 or 49°C) (Eckert 3rd et al 2006;Mazario and Basbaum 2007), and a significant enhancement of afterdischarge responses to 41 and 45°C (Martin et al 2004) after application of AITC (10%, ϳ60 l) to the hindpaw. Lamina I NS neuronal responses to heat were also enhanced post-AITC (Eckert 3rd et al 2006;Mazario and Basbaum 2007). Our results are generally consistent, in that AITC more strongly enhanced rat WDR neuronal responses to the lower stimulus temperatures (42 and 46°C) compared with the highest (50°C).…”

Section: Aitc and Ca Sensitization Of Heat-evoked Responsesmentioning

confidence: 91%

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Effects of TRPA1 Agonists Mustard Oil and Cinnamaldehyde on Lumbar Spinal Wide-Dynamic Range Neuronal Responses to Innocuous and Noxious Cutaneous Stimuli in Rats

Merrill

Cuéllar

Judd

et al. 2008

Journal of Neurophysiology

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Effects of TRPA1 agonists mustard oil and cinnamaldehyde on lumbar spinal wide-dynamic range neuronal responses to innocuous and noxious cutaneous stimuli in rats. J Neurophysiol 99: 415-425, 2008. First published October 17, 2007 doi:10.1152/jn.00883.2007. Mustard oil [allyl isothiocyanate (AITC)] and cinnamaldehyde (CA), agonists of the ion channel TRPA1 expressed in sensory neurons, elicit a burning sensation and heat hyperalgesia. We tested whether these phenomena are reflected in the responses of lumbar spinal wide-dynamic range (WDR) neurons recorded in pentobarbital-anesthetized rats. Responses to electrical and graded mechanical and noxious thermal stimulation were tested before and after cutaneous application of AITC or CA. Repetitive application of AITC initially increased the firing rate of 52% of units followed by rapid desensitization that persisted when AITC was reapplied 30 min later. Responses to noxious thermal, but not mechanical, stimuli were significantly enhanced irrespective of whether the neuron was directly activated by AITC. Windup elicited by percutaneous or sciatic nerve electrical stimulation was significantly reduced post-AITC. These results indicate that AITC produced central inhibition and peripheral sensitization of heat nociceptors. CA did not directly excite WDR neurons, and significantly enhanced responses to noxious heat while not affecting windup or responses to skin cooling or mechanical stimulation, indicating a peripheral sensitization of heat nociceptors. I N T R O D U C T I O NMustard oil [allyl isothiocyanate (AITC)] and cinnamic aldehyde (CA) are agonists of the transient receptor potential (TRP) channel TRPA1 (Bandell et al. 2004;Bautista et al. 2006;Jordt et al. 2004). When applied to skin, they elicit burning pain, thermal hyperalgesia, and mechanical allodynia (Koltzenburg et al. 1992;Namer et al. 2005). In the oral or nasal mucosa, AITC and CA elicit burning irritation that decreases (desensitizes) across trials of repeated application (Brand and Jacquot 2002;Prescott and Swain-Campbell 2000;Simons et al. 2003), as well as heat hyperalgesia (Albin et al. 2007). Lingual application of AITC or CA excites neurons in the trigeminal subnucleus caudalis (Vc) Simons et al. 2004;Zanotto et al. 2007). AITC excitation of Vc neurons exhibits a desensitizing temporal pattern while sensitizing responses to noxious heat (Simons et al. 2004). We presently tested whether spinal wide-dynamic range (WDR)-type dorsal horn neuronal responses to repeated cutaneous application of AITC or CA similarly exhibit a desensitizing pattern and whether their responses to mechanical and noxious thermal stimuli are enhanced after application of these chemicals, consistent with human psychophysical observations. We presently focused on WDR neurons for two reasons. First, WDR neurons respond to innocuous mechanical as well as noxious thermal stimuli, allowing assessment of the effects of AITC and CA on both types of responses within the same neuronal population, which would not be possible with no...

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Section: Mechanically and Electrically Evoked Responsessupporting

confidence: 90%

Section: Aitc and Ca Sensitization Of Heat-evoked Responsesmentioning

confidence: 91%

Effects of TRPA1 Agonists Mustard Oil and Cinnamaldehyde on Lumbar Spinal Wide-Dynamic Range Neuronal Responses to Innocuous and Noxious Cutaneous Stimuli in Rats

Merrill

Cuéllar

Judd

et al. 2008

Journal of Neurophysiology

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“…Apparently, heat and mechanical sensitization are dissociable and likely controlled by different mechanisms, as suggested by several other studies (Tal and Bennett, 1994;Ali et al, 1996;Mazarío and Basbaum, 2007). However, our behavioral results contradict the findings of Nassar et al (2004), who reported that sensitization to mechanical stimuli was absent after CFA in the same line of Na v 1.7 cKO mice that was used here.…”

Section: Discussioncontrasting

confidence: 54%

Sodium Channel Na_v1.7 Is Essential for Lowering Heat Pain Threshold after Burn Injury

Shields

Cheng

Üçeyler³

et al. 2012

J. Neurosci.

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Marked hypersensitivity to heat and mechanical (pressure) stimuli develop after a burn injury, but the neural mechanisms underlying these effects are poorly understood. In this study, we establish a new mouse model of focal second-degree burn injury to investigate the molecular and cellular basis for burn injury-induced pain. This model features robust injury-induced behavioral effects and tissuespecific altered cytokine profile, but absence of glial activation in spinal dorsal horn. Three voltage-gated sodium channels, Na v 1.7, Na v 1.8, and Na v 1.9, are preferentially expressed in peripheral somatosensory neurons of the dorsal root ganglia (DRGs) and have been implicated in injury-induced neuronal hyperexcitability. Using knock-out mice, we provide evidence that Na v 1.7 selectively contributes to burn-induced hypersensitivity to heat, but not mechanical, stimuli. After burn model injury, wild-type mice display increased sensitivity to heat stimuli, and a normally non-noxious warm stimulus induces activity-dependent Fos expression in spinal dorsal horn neurons. Strikingly, both effects are absent in Na v 1.7 conditional knock-out (cKO) mice. Furthermore, burn injury increases density and shifts activation of tetrodotoxin-sensitive currents in a hyperpolarized direction, both pro-excitatory properties, in DRG neurons from wild-type but not Na v 1.7 cKO mice. We propose that, in sensory neurons damaged by burn injury to the hindpaw, Na v 1.7 currents contribute to the hyperexcitability of sensory neurons, their communication with postsynaptic spinal pain pathways, and behavioral thresholds to heat stimuli. Our results offer insights into the molecular and cellular mechanisms of modality-specific pain signaling, and suggest Na v 1.7-blocking drugs may be effective in burn patients.

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“…Lamina I and V neurons in mice that lack Sub P exhibit deficits in their response to noxious heat, but not to noxious mechanical stimulation. In addition, in mice lacking Sub P, MO-induced sensitization to heat stimuli was greatly reduced in these neurons, whereas sensitization to mechanical stimuli was retained (Mazario and Basbaum, 2007). Interestingly, Simone and colleagues recently reported that ablation of NK1 expressing RVM neurons by microinjection of saporin-Sub P more effectively reduced capsaicin- and CFA-induced thermal hyperalgesia than mechanical hypersensitivity (Brink et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Effects of neurokinin-1 receptor agonism and antagonism in the rostral ventromedial medulla of rats with acute or persistent inflammatory nociception

2010

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The rostral ventromedial medulla (RVM), a central relay in the bulbospinal pathways that modulate nociception, contains high concentrations of Substance P (Sub P) and neurokinin-1 (NK1) receptors. However, the function of Sub P in the RVM is poorly understood. This study characterized the actions of Sub P in the RVM in the absence of injury and then used two NK1 receptor antagonists, L-733,060 and L-703, 606, to probe the role of endogenously released Sub P in the development and maintenance of persistent inflammatory nociception of immune or neurogenic origin. In uninjured rats, microinjection of Sub P in the RVM produced a transient thermal antinociception that was attenuated by pretreatment with L-733,060 or L-703,606. It did not alter threshold to withdrawal from tactile stimulation with von Frey filaments. Microinjection of the antagonists alone did not alter paw withdrawal latency or threshold suggesting that Sub P is not tonically released in the RVM in the absence of injury. However, microinjection of either antagonist in the RVM was sufficient to reverse heat hyperalgesia 4 h, 4 days or 2 weeks after intraplantar injection of complete Freund’s adjuvant (CFA). Antagonism of NK1 receptors in the RVM did not prevent or reverse tactile hypersensitivity induced by CFA, but did attenuate that produced by capsaicin. NK1 receptor antagonism did not prevent the development of thermal hyperalgesia, tactile hypersensitivity or spontaneous pain behaviors induced by mustard oil. The results suggest that Sub P has bimodal actions in the RVM and that following inflammatory injury, it can play a critical role as a pronociceptive agent in the development and maintenance of hyperalgesia and tactile hypersensitivity. However, its actions are highly dependent on the stimulus modality and the type of injury, and this may be an additional basis for the poor efficacy of NK1 receptor antagonists in clinical trials.

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Contribution of Substance P and Neurokinin A to the Differential Injury-Induced Thermal and Mechanical Responsiveness of Lamina I and V Neurons

Cited by 17 publications

References 36 publications

Effects of TRPA1 Agonists Mustard Oil and Cinnamaldehyde on Lumbar Spinal Wide-Dynamic Range Neuronal Responses to Innocuous and Noxious Cutaneous Stimuli in Rats

Effects of TRPA1 Agonists Mustard Oil and Cinnamaldehyde on Lumbar Spinal Wide-Dynamic Range Neuronal Responses to Innocuous and Noxious Cutaneous Stimuli in Rats

Sodium Channel Na_v1.7 Is Essential for Lowering Heat Pain Threshold after Burn Injury

Effects of neurokinin-1 receptor agonism and antagonism in the rostral ventromedial medulla of rats with acute or persistent inflammatory nociception

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Contribution of Substance P and Neurokinin A to the Differential Injury-Induced Thermal and Mechanical Responsiveness of Lamina I and V Neurons

Cited by 17 publications

References 36 publications

Effects of TRPA1 Agonists Mustard Oil and Cinnamaldehyde on Lumbar Spinal Wide-Dynamic Range Neuronal Responses to Innocuous and Noxious Cutaneous Stimuli in Rats

Effects of TRPA1 Agonists Mustard Oil and Cinnamaldehyde on Lumbar Spinal Wide-Dynamic Range Neuronal Responses to Innocuous and Noxious Cutaneous Stimuli in Rats

Sodium Channel Nav1.7 Is Essential for Lowering Heat Pain Threshold after Burn Injury

Effects of neurokinin-1 receptor agonism and antagonism in the rostral ventromedial medulla of rats with acute or persistent inflammatory nociception

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Sodium Channel Na_v1.7 Is Essential for Lowering Heat Pain Threshold after Burn Injury