Persistent hindlimb inflammation induces changes in activation properties of hyperpolarization-activated current (Ih) in rat C-fiber nociceptors in vivo

Djouhri, Laiche; Otaibi, M. Al; Kahlat, Karima; Smith, Trevor; Sathish, Jean G.; Weng, Xiechuan

doi:10.1016/j.neuroscience.2015.05.074

Cited by 27 publications

(21 citation statements)

References 63 publications

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“…In inflammatory pain models, HCN2 up-regulation in cell bodies and terminals of nociceptive neurons has been shown to occur as early as 24 h following induction of inflammation [103,104,106,128,145,146], in tandem with an increase in I h and C-fibre hyperexcitability [106,147]. The result of a nociceptive membrane more densely packed with HCN2 channels would be an increased net inward current upon HCN2 activation during the AP cycle, favouring higher rates of firing.…”

Section: How Does Augmented Hcn2 Activity Enhance Nociceptive Firing?mentioning

confidence: 99%

HCN2 ion channels: basic science opens up possibilities for therapeutic intervention in neuropathic pain

Tsantoulas

Mooney

McNaughton

2016

Biochemical Journal

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Nociception - the ability to detect painful stimuli - is an invaluable sense that warns against present or imminent damage. In patients with chronic pain, however, this warning signal persists in the absence of any genuine threat and affects all aspects of everyday life. Neuropathic pain, a form of chronic pain caused by damage to sensory nerves themselves, is dishearteningly refractory to drugs that may work in other types of pain and is a major unmet medical need begging for novel analgesics. Hyperpolarisation-activated cyclic nucleotide (HCN)-modulated ion channels are best known for their fundamental pacemaker role in the heart; here, we review data demonstrating that the HCN2 isoform acts in an analogous way as a 'pacemaker for pain', in that its activity in nociceptive neurons is critical for the maintenance of electrical activity and for the sensation of chronic pain in pathological pain states. Pharmacological block or genetic deletion of HCN2 in sensory neurons provides robust pain relief in a variety of animal models of inflammatory and neuropathic pain, without any effect on normal sensation of acute pain. We discuss the implications of these findings for our understanding of neuropathic pain pathogenesis, and we outline possible future opportunities for the development of efficacious and safe pharmacotherapies in a range of chronic pain syndromes.

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Section: How Does Augmented Hcn2 Activity Enhance Nociceptive Firing?mentioning

confidence: 99%

HCN2 ion channels: basic science opens up possibilities for therapeutic intervention in neuropathic pain

Tsantoulas

Mooney

McNaughton

2016

Biochemical Journal

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“…These channels are known to be regulated in inflammatory pain (Emery et al, 2012; Weng et al, 2012; Rahman and Dickenson, 2013; Waxman and Zamponi, 2014), suggesting that C fiber ADS may be altered in inflammatory pain. Specifically, CFA inflammation increases both hyperpolarization-activated current ( I h ) and HCN2 expression levels in C fiber nociceptors (Papp et al, 2010; Acosta et al, 2012; Weng et al, 2012) and alters I h activation properties (Djouhri et al, 2015). Furthermore, deletion of HCN2 in Nav1.8-expressing neurons, which are mainly C fiber nociceptors, limits inflammatory thermal hyperalgesia (Emery et al, 2011), and peripheral block of HCN channels attenuates inflammatory pain (Young et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Inflammatory Pain Reduces C Fiber Activity-Dependent Slowing in a Sex-Dependent Manner, Amplifying Nociceptive Input to the Spinal Cord

et al. 2017

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C fibers display activity-dependent slowing (ADS), whereby repetitive stimulation (≥1 Hz) results in a progressive slowing of action potential conduction velocity, which manifests as a progressive increase in response latency. However, the impact of ADS on spinal pain processing has not been explored, nor whether ADS is altered in inflammatory pain conditions. To investigate, compound action potentials were made, from dorsal roots isolated from rats with or without complete Freund's adjuvant (CFA) hindpaw inflammation, in response to electrical stimulus trains. CFA inflammation significantly reduced C fiber ADS at 1 and 2 Hz stimulation rates. Whole-cell patch-clamp recordings in the spinal cord slice preparation with attached dorsal roots also demonstrated that CFA inflammation reduced ADS in the monosynaptic C fiber input to lamina I neurokinin 1 receptor-expressing neurons (1–10 Hz stimulus trains) without altering the incidence of synaptic response failures. When analyzed by sex, it was revealed that females display a more pronounced ADS that is reduced by CFA inflammation to a level comparable with males. Cumulative ventral root potentials evoked by long and short dorsal root stimulation lengths, to maximize and minimize the impact of ADS, respectively, demonstrated that reducing ADS facilitates spinal summation, and this was also sex dependent. This finding correlated with the behavioral observation of increased noxious thermal thresholds and enhanced inflammatory thermal hypersensitivity in females. We propose that sex/inflammation-dependent regulation of C fiber ADS can, by controlling the temporal relay of nociceptive inputs, influence the spinal summation of nociceptive signals contributing to sex/inflammation-dependent differences in pain sensitivity.SIGNIFICANCE STATEMENT The intensity of a noxious stimulus is encoded by the frequency of action potentials relayed by nociceptive C fibers to the spinal cord. C fibers conduct successive action potentials at progressively slower speeds, but the impact of this activity-dependent slowing (ADS) is unknown. Here we demonstrate that ADS is more prevalent in females than males and is reduced in an inflammatory pain model in females only. We also demonstrate a progressive delay of C fiber monosynaptic transmission to the spinal cord that is similarly sex and inflammation dependent. Experimentally manipulating ADS strongly influences spinal summation consistent with sex differences in behavioral pain thresholds. This suggests that ADS provides a peripheral mechanism that can regulate spinal nociceptive processing and pain sensation.

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“…As described previously (e.g. Djouhri et al., , , , ; Smith, Al Otaibi, Sathish, & Djouhri, ; Weng et al., ), the withdrawal latencies were the average of three trials obtained from each hind paw, and heat hypersensitivity (hyperalgesia) was indicated by a significant decrease in the mean paw withdrawal latency (PWL).…”

Section: Methodsmentioning

confidence: 90%

“…The in vivo electrophysiological experiments were conducted in deeply anesthetized rats as described previously (Djouhri et al., , , ; Weng et al., ). Briefly, a tracheotomy was performed to allow artificial ventilation and monitoring of end‐tidal CO 2 , which was maintained between 3 and 4% by adjusting the volume and rate of the respiratory pump.…”

Section: Methodsmentioning

confidence: 99%

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Membrane potential oscillations are not essential for spontaneous firing generation in L4 Aβ‐afferent neurons after L5 spinal nerve axotomy and are not mediated by HCN channels

Djouhri

Smith

Alotaibi

et al. 2018

Experimental Physiology

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The underlying cellular and molecular mechanisms of peripheral neuropathic pain are not fully understood. However, preclinical studies using animal models suggest that this debilitating condition is driven partly by aberrant spontaneous activity (SA) in injured and uninjured dorsal root ganglion (DRG) neurons, and that SA in injured DRG neurons is triggered by subthreshold membrane potential oscillations (SMPOs). Here, using in vivo intracellular recording from control L4-DRG neurons, and ipsilateral L4-DRG neurons in female Wistar rats that had previously undergone L5 spinal nerve axotomy (SNA), we examined whether conducting 'uninjured' L4-DRG neurons in SNA rats exhibit SMPOs, and if so, whether such SMPOs are associated with SA in those L4 neurons, and whether they are mediated by hyperpolarization-activated cyclic nucleotide gated (HCN) channels. We found that 7 days after SNA: (a) none of the control A- or C-fibre DRG neurons showed SMPOs or SA, but 50%, 43% and 0% of spontaneously active cutaneous L4 Aβ-low threshold mechanoreceptors, Aβ-nociceptors and C-nociceptors exhibited SMPOs, respectively, in SNA rats with established neuropathic pain behaviors; (b) neither SMPOs nor SA in L4 Aβ-neurons was suppressed by blocking HCN channels with ZD7288 (10 mg kg , i.v.); and (c) there is a tendency for female rats to show greater pain hypersensitivity than male rats. These results suggest that SMPOs are linked to SA only in some of the conducting L4 Aβ-neurons, that such oscillations are not a prerequisite for SA generation in those L4 A- or C-fibre neurons, and that HCN channels are not involved in their electrogenesis.

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Persistent hindlimb inflammation induces changes in activation properties of hyperpolarization-activated current (Ih) in rat C-fiber nociceptors in vivo

Cited by 27 publications

References 63 publications

HCN2 ion channels: basic science opens up possibilities for therapeutic intervention in neuropathic pain

HCN2 ion channels: basic science opens up possibilities for therapeutic intervention in neuropathic pain

Inflammatory Pain Reduces C Fiber Activity-Dependent Slowing in a Sex-Dependent Manner, Amplifying Nociceptive Input to the Spinal Cord

Membrane potential oscillations are not essential for spontaneous firing generation in L4 Aβ‐afferent neurons after L5 spinal nerve axotomy and are not mediated by HCN channels

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