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

• Type: Article in International Scientific Journal
• Date: 2020

Authors

Costa, AR (Author) Other; sousa, m (Author) ICBAS; Wilson, SP (Author) Other; reguenga, c (Author) FMUP; Teixeira Pinto, A (Author) Other; Isaura Tavares (Author) FMUP; Maria Isabel Martins (Author) FMUP

Journal

Title: Anesthesiology

Vol. 133

Pages: 628-644

ISSN: 0003-3022

Publisher: Wolters Kluwer Health

Indexing

ISI Web of Knowledge - 5 Citations

Scopus - 9 Citations

Other information

Authenticus ID: P-00S-P2D

DOI: 10.1097/aln.0000000000003412

Abstract (EN): Background: Increased descending pain facilitation accounts for opioid-induced hyperalgesia, but the underlying mechanisms remain elusive. Given the role of mu-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 mu-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 mu-opioid receptor and phosphorylated cAMP response element-binding, a downstream marker of excitatory mu-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 mu-opioid receptor, without concomitant messenger RNA changes, and phosphorylated cAMP response element-binding levels at the dorsal reticular nucleus. mu-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). mu-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 mu-opioid receptor agonist (D-ALA2,N-ME-PHE4,GLY5-OL)-enkephalin acetate (DAMGO) decreased mechanical thresholds and did not affect heatevoked 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 mu-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 mu-opioid receptor signaling from inhibitory to excitatory at the dorsal reticular nucleus, likely enhancing descending facilitation during opioid-induced hyperalgesia in the rat.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 17