Peripheral Administration of Translation Inhibitors Reverses Increased Hyperalgesia in a Model of Chronic Pain in the Rat

Abstract

Chronic pain is extremely difficult to manage, in part due to lack of progress in reversing the underlying pathophysiology. Since translation of mRNAs in the peripheral terminal of the nociceptor plays a role in the transition from acute to chronic pain, we tested the hypothesis that transient inhibition of translation in the peripheral terminal of the nociceptor could reverse hyperalgesic priming, a model of transition from acute to chronic pain. We report that injection of translation inhibitors, rapamycin and cordycepin, which inhibit translation by different mechanisms, at the peripheral terminal of the primed nociceptor, produce reversal of priming, in the rat, that outlasted the duration of action of these drugs to prevent the development of priming. These data support the suggestion that interruption of translation in the nociceptor can reverse a preclinical model of at least one form of chronic pain.

Curcumin Treatment Attenuates Pain and Enhances Functional Recovery after Incision

“…This form of latent sensitization is believed to be mediated by both peripheral effects in the primary afferent fiber nerve terminals and neuroplastic events within the spinal cord. 44,57,58 With respect to ongoing pain, curcumin was effective in eliminating evidence of ongoing pain in the CPP paradigm. Detailed electrophysiological studies have linked spontaneous afferent discharges and sensitization to spontaneous pain-related behaviors after hindpaw incision.…”

Translational Control Mechanisms in Persistent Pain

“…A solution that has emerged to solve this biological riddle is localized translation at nociceptor endings and/or along injured axons to control changes in gene expression. This solution is important because: (i) it explains how many endogenous pain-promoting molecules induce long-lasting plasticity [1–10]; (ii) it is supported by findings from experimental pain models in humans that are best explained by localized translation regulation [11,12]; and (iii) it provides insight into the generation of ectopic activity after peripheral nerve injury [6,13–16], which is a major driver of neuropathic pain . In this review, we summarize rapidly growing, recent literature that elucidates the intricacies of translational control in persistent pain and highlight new therapeutic opportunities.…”

“…In the dorsal horn of the spinal cord, the activation of mTOR and ERK pathways has been well documented following peripheral inflammation and nerve injury [15,42–49]. Peripheral (subcutaneous) and central (intrathecal) administration of rapamycin, an allosteric mTORC1 inhibitor, and its paralogs, effectively reduces mechanical hypersensitivity in models of nerve injury, inflammation, cancer pain, and postsurgical pain [1,5,9,15,37,41,44,50–52]. The activation of mTORC1 has also been detected in the spinal cord dorsal horn following repeated opioid administration [7].…”

Balancing GRK2 and EPAC1 levels prevents and relieves chronic pain

“…Earlier studies have shown that activation of the mTOR pathway and protein translation in the periphery are required for development of IL-6-and carrageenan-induced priming of the subsequent response to PGE 2 (10,11,17,39). Axonal protein synthesis under the control of mTOR and ERK activation contribute to chronic pain in multiple other models as well (12)(13)(14).…”