Toward a New Class of Analgesics for Neuropathic Pain

Peripheral neuropathic pain is commonly managed pharmacologically through administration of sodium channel blockers that prevent neuronal excitation. Because these local anesthetics are not specific to sensory neurons, they are accompanied with major adverse effects that include paralysis and failure of autonomic responses.

The seriousness of these side effects has prompted the search for improved pharmacological agents with increased selectivity for transient receptor potential vanilloid 1 (TRPV1)-expressing primary sensory nociceptors.¹

Impaired conduction along A_α/β and C fibers has been implicated in chronic neuropathic pain, osteoarthritis, and painful diabetic neuropathy.^2-4 In a study recently published in Pain, scientists sought to investigate whether altered conduction along nociceptive C-fibers had an impact on analgesia.⁵

Based on their previous findings,⁴ the authors hypothesized that the observed disruption of conduction along C-fibers “may serve as an intrinsic self-inhibitory mechanism for the modulation of persistent nociceptive input along nociceptive C-fibers,” and that “targeting the factors involved in conduction failure might therefore represent a new therapeutic target for the treatment of abnormal peripheral pain.”

Administration of ZD7288, an antagonist of hyperpolarization-activated cyclic nucleotide-modulated (HCN) channels, widely expressed on nociceptive neurons, was shown to have an analgesic effect on several animal models of pain, including models of inflammatory and neuropathic pain.⁶

As ZD7288 also binds HCN channels on non-nociceptors, thus causing bradycardia, the researchers sought to determine whether local administration of the compound could efficiently block conduction along C-fibers, thereby producing an analgesic effect.

To produce an animal model of C-fiber-mediated inflammatory pain, rats were injected with complete Freund’s adjuvant (CFA), either subcutaneously in the distal tail or intradermally in the hindlimb, within the receptive fields of dorsal root ganglia (L4 and L5 levels). 

Conduction along polymodal C-fibers was affected in a frequency-dependent manner following CFA injection, as assessed by single fiber recordings within the coccygeal nerve. Administration of the HCN antagonist further reduced conduction velocity in a dose-dependent manner. In addition, ZD7288 reduced spontaneous firing, which is observed in about 20% of polymodal C-fibers, and thought of as a “surrogate indicator of spontaneous pain.”

The effect of the HCN antagonist on conduction failure was further investigated and found to primarily occur in small- but not large-diameter nociceptive fibers within dorsal root ganglia.

In addition, CFA- and formalin-evoked pain behaviors (ie, mechanical allodynia and hyperalgesia) were alleviated following perisciatic injection of ZD7288, indicating that analgesia can be achieved by local vs systemic administration of the agent, thus limiting adverse effects such as motor deficits and bradycardia observed following a similar injection of lidocaine.

Because the HCN antagonist selectively reduces conduction along small-diameter C-fibers, the mechanisms of action of this compound—which scientists started to uncover in this study—offer a new avenue for the development of peripheral analgesics that have the potential to block afferent nociceptive inputs and produce minimal adverse effects.

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References

1. Binshtok AM, Bean BP, Woolf CJ. Inhibition of nociceptors by TRPV1-mediated entry of impermeant sodium channel blockers. Nature. 2007;449(7162):607-610.
2. Tsantoulas C, Zhu L, Yip P, Grist J, Michael GJ, Mcmahon SB. Kv2 dysfunction after peripheral axotomy enhances sensory neuron responsiveness to sustained input. Exp Neurol. 2014;251:115-126.
3. Wu Q, Henry JL. Peripheral drive in Aα/β-fiber neurons is altered in a rat model of osteoarthritis: changes in following frequency and recovery from inactivation. J Pain Res. 2013;6:207-221.
4. Sun W, Miao B, Wang XC, et al. Reduced conduction failure of the main axon of polymodal nociceptive C-fibres contributes to painful diabetic neuropathy in rats. Brain. 2012;135(Pt 2):359-375.
5. Wang X, Wang S, Wang W, et al. A novel intrinsic analgesic mechanism: the enhancement of the conduction failure along polymodal nociceptive C-fibers. Pain. 2016;157(10):2235-2247.
6. Emery EC, Young GT, Berrocoso EM, Chen L, Mcnaughton PA. HCN2 ion channels play a central role in inflammatory and neuropathic pain. Science. 2011;333(6048):1462-1466.