Hyperpolarization-activated cyclic nucleotide–gated channels contribute to spontaneous activity in L4 C-fiber nociceptors, but not Aβ-non-nociceptors, after axotomy of L5-spinal nerve in the rat in vivo

Djouhri, Laiche; Smith, Trevor; Ahmeda, Ahmad; Alotaibi, Mashael Alhumaidi; Weng, Xiechuan

doi:10.1097/j.pain.0000000000001224

Cited by 22 publications

(25 citation statements)

References 61 publications

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“…The I h has been recognized to be carried by channels of the HCN gene family, namely HCN1, HCN2, HCN3 and HCN4 [10]. It has been recently demonstrated that HCN1, HCN2 or HCN3 channels play essential roles in sensory excitability and pain sensation [30,38,40]. Regardless of the detailed mechanism of their inhibitory actions, there is likely to be a relevant link between the effects of these croton derivatives on electrically excitable cells and their inhibitory effects on HCN channel activity, though croton-03-mediated effect on HCN channels might not be isoform-specific.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Inhibitory Effectiveness in Hyperpolarization-Activated Cation Currents by a Group of ent-Kaurane-Type Diterpenoids from Croton tonkinensis

Kuo

Liu

et al. 2020

IJMS

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Croton is an extensive flowering plant genus in the spurge family, Euphorbiaceae. Three croton compounds with the common ent-kaurane skeleton have been purified from Croton tonkinensis. Methods: We examined any modifications of croton components (i.e., croton-01 [ent-18-acetoxy-7α-hydroxykaur-16-en-15-one], croton-02 [ent-7α,14β-dihydroxykaur-16-en-15-one] and croton-03 [ent-1β-acetoxy-7α,14β-dihydroxykaur-16-en-15-one] on either hyperpolarization-activated cation current (Ih) or erg-mediated K+ current identified in pituitary tumor (GH3) cells and in rat insulin-secreting (INS-1) cells via patch-clamp methods. Results: Addition of croton-01, croton-02, or croton-03 effectively and differentially depressed Ih amplitude. Croton-03 (3 μM) shifted the activation curve of Ih to a more negative potential by approximately 11 mV. The voltage-dependent hysteresis of Ih was also diminished by croton-03 administration. Croton-03-induced depression of Ih could not be attenuated by SQ-22536 (10 μM), an inhibitor of adenylate cyclase, but indeed reversed by oxaliplatin (10 μM). The Ih in INS-1 cells was also depressed effectively by croton-03. Conclusion: Our study highlights the evidence that these ent-kaurane diterpenoids might conceivably perturb these ionic currents through which they have high influence on the functional activities of endocrine or neuroendocrine cells.

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Section: Discussionmentioning

confidence: 99%

Characterization of Inhibitory Effectiveness in Hyperpolarization-Activated Cation Currents by a Group of ent-Kaurane-Type Diterpenoids from Croton tonkinensis

Kuo

Liu

et al. 2020

IJMS

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“…This means finding a spontaneously firing neuron requires 4 or more successful experiments with at least 4 neurons in each experiment. Full details of the animal preparation were as reported previously (Djouhri et al, 2018). Briefly, to allow artificial ventilation and monitoring of end-tidal CO 2 , a tracheotomy was performed.…”

Section: In Vivo Electrophysiological Recordingsmentioning

confidence: 99%

“…The left jugular vein and carotid artery were tabulated to enable, respectively, regular injections of additional doses of anesthetic (sodium pentobaribtone 10mg/kg) and monitoring of blood pressure (normally ∼80-100 mmHg). A laminectomy was performed from vertebrae L2-L6 as reported previously (Djouhri et al, 2018). Intracellular voltage recordings from somata of L4 or L5 DRG neurons were obtained using sharp glass microelectrodes filled with 3M or 1M KCl.…”

Section: In Vivo Electrophysiological Recordingsmentioning

confidence: 99%

Cutaneous Aβ-Non-nociceptive, but Not C-Nociceptive, Dorsal Root Ganglion Neurons Exhibit Spontaneous Activity in the Streptozotocin Rat Model of Painful Diabetic Neuropathy in vivo

et al. 2020

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Diabetic peripheral neuropathic pain (DPNP) is the most devastating complication of diabetes mellitus. Unfortunately, successful therapy for DPNP remains a challenge because its pathogenesis is still elusive. However, DPNP is believed to be due partly to abnormal hyperexcitability of dorsal root ganglion (DRG) neurons, but the relative contributions of specific functional subtypes remain largely unknown. Here, using the strepotozotocin (STZ) rat model of DPNP induced by a STZ injection (60 mg/kg, i.p), and intracellular recordings of action potentials (APs) from DRG neurons in anesthetized rats, we examined electrophysiological changes in C-and Aβ-nociceptive and Aβ-low threshold mechanoreceptive (LTM) neurons that may contribute to DPNP. Compared with control, we found in STZ-rats with established pain hypersensitivity (5 weeks post-STZ) several significant changes including: (a) A 23% increase in the incidence of spontaneous activity (SA) in Aβ-LTMs (but not C-mechanosensitive nociceptors) that may cause dysesthesias/paresthesia suffered by DPNP patients, (b) membrane hyperpolarization and a ∼85% reduction in SA rate in Aβ-LTMs by K v 7 channel activation with retigabine (6 mg/kg, i.v.) suggesting that K v 7/M channels may be involved in mechanisms of SA generation in Aβ-LTMs, (c) decreases in AP duration and in duration and amplitude of afterhyperpolarization (AHP) in C-and/or Aβ-nociceptors. These faster AP and AHP kinetics may lead to repetitive firing and an increase in afferent input to the CNS and thereby contribute to DPNP development, and (d) a decrease in the electrical thresholds of Aβ-nociceptors that may contribute to their sensitization, and thus to the resulting hypersensitivity associated with DPNP.

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“…Intracellular recordings from DRG neurons both ex vivo and in vitro confirmed that peripheral nerve injury increases their excitability and may provoke spontaneous discharge of action potentials (Study and Kral, 1996;Djouhri et al, 2018). In a study of the effect of complete nerve section, we found and that the most profound increases were seen in animals that displayed autotomy (Abdulla and Smith, 2001a).…”

Section: Role Of Increased Peripheral Neuron Excitability and Dorsal mentioning

confidence: 59%

K+ Channels in Primary Afferents and Their Role in Nerve Injury-Induced Pain

Smith

2020

Front. Cell. Neurosci.

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Sensory abnormalities generated by nerve injury, peripheral neuropathy or disease are often expressed as neuropathic pain. This type of pain is frequently resistant to therapeutic intervention and may be intractable. Numerous studies have revealed the importance of enduring increases in primary afferent excitability and persistent spontaneous activity in the onset and maintenance of peripherally induced neuropathic pain. Some of this activity results from modulation, increased activity and /or expression of voltage-gated Na + channels and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. K + channels expressed in dorsal root ganglia (DRG) include delayed rectifiers (K v 1.1, 1.2), A-channels (K v 1.4, 3.3, 3.4, 4.1, 4.2, and 4.3), KCNQ or M-channels (K v 7.2, 7.3, 7.4, and 7.5), ATP-sensitive channels (K IR 6.2), Ca 2+-activated K + channels (K Ca 1.1, 2.1, 2.2, 2.3, and 3.1), Na +-activated K + channels (K Ca 4.1 and 4.2) and two pore domain leak channels (K 2p ; TWIK related channels). Function of all K + channel types is reduced via a multiplicity of processes leading to altered expression and/or post-translational modification. This also increases excitability of DRG cell bodies and nociceptive free nerve endings, alters axonal conduction and increases neurotransmitter release from primary afferent terminals in the spinal dorsal horn. Correlation of these cellular changes with behavioral studies provides almost indisputable evidence for K + channel dysfunction in the onset and maintenance of neuropathic pain. This idea is underlined by the observation that selective impairment of just one subtype of DRG K + channel can produce signs of pain in vivo. Whilst it is established that various mediators, including cytokines and growth factors bring about injury-induced changes in DRG function and excitability, evidence presently available points to a seminal role for interleukin 1β (IL-1β) in control of K + channel function. Despite the current state of knowledge, attempts to target K + channels for therapeutic pain management have met with limited success. This situation may change with the advent of personalized medicine. Identification of specific sensory abnormalities and genetic profiling of individual patients may predict therapeutic benefit of K + channel activators.

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Hyperpolarization-activated cyclic nucleotide–gated channels contribute to spontaneous activity in L4 C-fiber nociceptors, but not Aβ-non-nociceptors, after axotomy of L5-spinal nerve in the rat in vivo

Cited by 22 publications

References 61 publications

Characterization of Inhibitory Effectiveness in Hyperpolarization-Activated Cation Currents by a Group of ent-Kaurane-Type Diterpenoids from Croton tonkinensis

Characterization of Inhibitory Effectiveness in Hyperpolarization-Activated Cation Currents by a Group of ent-Kaurane-Type Diterpenoids from Croton tonkinensis

Cutaneous Aβ-Non-nociceptive, but Not C-Nociceptive, Dorsal Root Ganglion Neurons Exhibit Spontaneous Activity in the Streptozotocin Rat Model of Painful Diabetic Neuropathy in vivo

K+ Channels in Primary Afferents and Their Role in Nerve Injury-Induced Pain

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