Shift of µ-opioid Receptor Signaling in the Dorsal Reticular Nucleus Is Implicated in Morphine-induced Hyperalgesia in Male Rats

Abstract

Background Increased descending pain facilitation accounts for opioid-induced hyperalgesia, but the underlying mechanisms remain elusive. Given the role of µ-opioid receptors in opioid-induced hyperalgesia in animals, the authors hypothesized that the dorsal reticular nucleus, a medullary pain facilitatory area, is involved in opioid-induced hyperalgesia through altered µ-opioid receptor signaling. Methods The authors used male Wistar rats (n = 5 to 8 per group), chronically infused with morphine, to evaluate in the dorsal reticular nucleus the expressions of the µ-opioid receptor and phosphorylated cAMP response element-binding, a downstream marker of excitatory µ-opioid receptor signaling. The authors used pharmacologic and gene-mediated approaches. Nociceptive behaviors were evaluated by the von Frey and hot-plates tests. Results Lidocaine fully reversed mechanical and thermal hypersensitivity induced by chronic morphine. Morphine-infusion increased µ-opioid receptor, without concomitant messenger RNA changes, and phosphorylated cAMP response element-binding levels at the dorsal reticular nucleus. µ-opioid receptor knockdown in morphine-infused animals attenuated the decrease of mechanical thresholds and heat-evoked withdrawal latencies compared with the control vector (von Frey [mean ± SD]: −17 ± 8% vs. −40 ± 9.0%; P < 0.001; hot-plate: −10 ± 5% vs. −32 ± 10%; P = 0.001). µ-opioid receptor knockdown in control animals induced the opposite (von Frey: −31 ± 8% vs. −17 ± 8%; P = 0.053; hotplate: −24 ± 6% vs. −3 ± 10%; P = 0.001). The µ-opioid receptor agonist (D-ALA2,N-ME-PHE4,GLY5-OL)-enkephalin acetate (DAMGO) decreased mechanical thresholds and did not affect heat-evoked withdrawal latencies in morphine-infused animals. In control animals, DAMGO increased both mechanical thresholds and heat-evoked withdrawal latencies. Ultra-low-dose naloxone, which prevents the excitatory signaling of the µ-opioid receptor, administered alone, attenuated mechanical and thermal hypersensitivities, and coadministered with DAMGO, restored DAMGO analgesic effects and decreased phosphorylated cAMP response element-binding levels. Conclusions Chronic morphine shifted µ-opioid receptor signaling from inhibitory to excitatory at the dorsal reticular nucleus, likely enhancing descending facilitation during opioid-induced hyperalgesia in the rat. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New