HDAC6 Inhibitors Blunt Pain by Upregulating Opioid Receptors
Jixiang Zhang, Jazzmine M. Junigan, Ronnie Trinh, Annemieke Kavelaars, Cobi J. Heijnen, et al.
(see pages 7862–7874)
Chemotherapy-induced peripheral neuropathy (CIPN) increases pain sensitivity and can produce spontaneous pain in the distal appendages of many cancer patients. The symptoms can persist for months or years after therapy has ended. No approved treatments for CIPN are currently available, but inhibitors of histone deacetylase 6 (HDAC6) are promising candidates. In rodent models of CIPN, HDAC6 inhibitors prevent or reverse mechanical hypersensitivity if given with or after treatment with the chemotherapeutic agent cisplatin. The reversal effect requires release of the cytokine IL-10 from macrophages and activation of IL-10 receptors in sensory neurons. Zhang et al. provide evidence that this effect also depends on increased signaling via delta opioid receptors (DORs) in sensory neurons.
In many rodent models of chronic pain, restoration of normal mechanical thresholds requires ongoing suppression of neuronal activity by opioid signaling: if opioid receptors are blocked, latent hypersensitivity is unmasked. Zhang et al. found that the same is true for the analgesic effect of HDAC6 inhibitors. Specifically, cisplatin administration lowered withdrawal thresholds, an HDAC6 inhibitor restored thresholds to control levels, and subsequent administration of a DOR-selective antagonist reinstated hypersensitivity. Antibodies targeting the endogenous DOR ligand encephalin also reinstated hypersensitivity, but selective antagonists of mu and kappa opioid receptors did not. Intriguingly, however, blocking opioid receptors did not interfere with the ability of HDAC6 inhibitors to prevent (rather than reverse) the development of hypersensitivity after cisplatin treatment.
In addition to lowering mechanical thresholds for withdrawal, cisplatin reduced expression of DORs (but not other opioid receptor subtypes) in dorsal root ganglion mechanoreceptors and nociceptors. Levels were restored to normal by inhibiting HDAC6. Finally, HDAC6 inhibitors failed to reverse cisplatin-induced hypersensitivity in mice in which DORs were knocked out selectively in sensory neurons, confirming the necessity of DOR signaling in these cells for CIPN reversal.
These results suggest that HDAC6 inhibitors restore expression of DORs in sensory neurons, allowing tonic activation of these receptors to suppress cisplatin-induced mechanical hypersensitivity. HDAC6 inhibitors must prevent the initial development of CIPN through other mechanisms, however. Future work should determine how cisplatin decreases DOR expression, and whether the restoration of DOR expression by HDAC6 inhibitors is mediated by IL-10 signaling.
Compared with control NMJs in Drosophila (top), those expressing ALS-related vapbP58S have fewer, but larger boutons. See Karagas et al. for details.
ALS-Linked Mutation Slows Postspike Calcium Extrusion
Nicholas E. Karagas, Richa Gupta, Elham Rastegari, Kai Li Tan, Ho Hang Leung, et al.
(see pages 8019–8037)
Mutations in more than 20 genes have been linked to autosomal dominant amyotrophic lateral sclerosis (ALS). One such gene encodes vesicle-associated membrane protein B (VAPB), which is rendered nonfunctional by a proline-to-serine switch at codon 56 (P56S). VAPB is an adaptor protein that resides in the endoplasmic reticulum (ER) membrane. Through interactions with numerous other proteins, it serves many functions; for example, it mediates interactions between the ER and other organelles, contributes to the ER unfolded-protein response, and tethers ER to microtubules. Notably, contacts between the ER and mitochondria influence ATP production and calcium homeostasis. Karagas et al. show that disruption of these processes contributes to loss of axonal boutons at neuromuscular junctions (NMJs) in Drosophila larvae expressing vapbP58S.
Previous work showed that knocking out vapb or expressing vapbP58S in Drosophila reduces the number and increases the size of presynaptic boutons at NMJs. Because a similar phenotype is produced by knocking out or overexpressing the ER calcium channel Inactive (Iav), Karagas et al. predicted that knocking out iav in vapbP58S-expressing larvae would exacerbate the phenotype. Unexpectedly, however, iav knockout rescued bouton number and size. Knocking out either of two other ER calcium channels—the ryanodine receptor or the inositol trisphosphate receptor—also rescued bouton number in vapbP58S-expressing larvae, as did inhibiting calcium/calmodulin-dependent kinase II (CaMKII). Inhibiting CaMKII also rescued bouton number in neurons overexpressing iav and rescued microtubule loop structures disrupted in boutons expressing vapbP58S.
The authors hypothesized that vapbP58S expression leads to elevation of intracellular calcium concentration, activating CaMKII, which has previously been shown to destabilize microtubules. Examination of synaptic vesicle release indicated that resting calcium levels were not elevated, however. Instead, vapbP58S delayed calcium extrusion after axon spiking. Calcium extrusion requires ATP, and additional experiments suggested ATP production in vapbP58S-expressing neurons is insufficient to keep up with demands from increased activity.
These results are consistent with a model in which loss of vapb function disrupts ER–mitochondrial interactions, resulting in inadequate production of ATP in spiking neurons. This, in turn, leads to delayed extrusion of calcium after spikes. Prolonged elevation of calcium leads to excessive activation of CaMKII, which phosphorylates microtubule-associated proteins, thus destabilizing microtubules and causing loss of synaptic boutons.
Footnotes
This Week in The Journal was written by Teresa Esch, Ph.D.
