Tiam1-mediated maladaptive plasticity underlying morphine tolerance and hyperalgesia.

Opioid pain medications, such as morphine, remain the mainstay for treating severe and chronic pain. Prolonged morphine use, however, triggers analgesic tolerance and hyperalgesia (OIH), which can last for a long period after morphine withdrawal. How morphine induces these detrimental side effects remains unclear. Here, we show that morphine tolerance and OIH are mediated by Tiam1-coordinated synaptic structural and functional plasticity in the spinal nociceptive network. Tiam1 is a Rac1 GTPase guanine nucleotide exchange factor that promotes excitatory synaptogenesis by modulating actin cytoskeletal dynamics. We found that prolonged morphine treatment activated Tiam1 in the spinal dorsal horn and Tiam1 ablation from spinal neurons eliminated morphine antinociceptive tolerance and OIH. At the same time, the pharmacological blockade of Tiam1-Rac1 signalling prevented the development and reserved the established tolerance and OIH. Prolonged morphine treatment increased dendritic spine density and synaptic NMDA receptor activity in spinal dorsal horn neurons, both of which required Tiam1. Furthermore, co-administration of the Tiam1 signalling inhibitor NSC23766 was sufficient to abrogate morphine tolerance in chronic pain management. These findings identify Tiam1-mediated maladaptive plasticity in the spinal nociceptive network as an underlying cause for the development and maintenance of morphine tolerance and OIH and provide a promising therapeutic target to reduce tolerance and prolong morphine use in chronic pain management.

Epidural Posterior Insular Stimulation Alleviates Neuropathic Pain Manifestations in Rats With Spared Nerve Injury Through Endogenous Opioid System.

OBJECTIVES: Neuropathic pain (NP) is defined as constant disabling pain secondary to a lesion or disease of the somatosensory nervous system. This condition is particularly difficult to treat because it often remains resistant to most treatment strategies. Despite the recent diversification of neurostimulation methods, some patients still suffer from refractory pain syndromes. The central role of the posterior insular cortex (PI) in the modulation of pain signaling and perception has been repeatedly suggested. The objective of this study is to assess whether epidural insular stimulation (IS) could reverse NP behavior. MATERIALS AND METHODS: A total of 53 adult Sprague-Dawley rats received left-sided spared nerve injury (SNI) or Sham-SNI to induce NP symptoms. Afterward, epidural electrodes were implanted over the right PI. After two weeks of postoperative recovery, three groups of SNI-operated rats each received a different stimulation modality: Sham-IS, low-frequency-IS (LF-IS), or high-frequency-IS (HF-IS). Behavioral and functional tests were conducted before and after IS. They comprised the acetone test, pinprick test, von Frey test, and sciatic functional index. An additional LF-IS group received a dose of opioid antagonist naloxone before IS. Intergroup means were compared through independent-samples t-tests, and pre- and post-IS means in the same group were compared through paired t-tests. RESULTS: We found a significant reduction of cold allodynia (p = 0.019), mechanical hyperalgesia (p = 0.040), and functional disability (p = 0.005) after LF-IS but not HF-IS. Mechanical allodynia only showed a tendency to decrease after LF-IS. The observed analgesic effects were reversed by opioid antagonist administration. CONCLUSION: These results suggest a significant reversal of NP symptoms after LF-IS and offer additional evidence that IS might be beneficial in the treatment of resistant NP syndromes through endogenous opioid secretion. Relying on our novel epidural IS model, further fine tuning of stimulation parameters might be necessary to achieve optimal therapeutic effects.