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

The long-term effects of repeated heroin vapor inhalation during adolescence on measures of nociception and anxiety-like behavior in adult Wistar rats

“…Opioid tolerance and opioid-induced hypersensitivity to noxious stimuli are commonly reported adverse effects of repeated opioid treatment (Allouche et al 2014;Célèrier et al 2001;Colvin et al 2019;Costa et al 2020;Doyle et al 2020;Gardell et al 2006;Vanderah et al 2001). The development of tolerance to opioids can lead to dose escalation in patients in clinical settings (Han et al 2013) and in illicit opioid users (Cowan et al 2001).…”

Knowing the Enemy Is Halfway towards Victory: A Scoping Review on Opioid-Induced Hyperalgesia

“…MOR is a transmembrane G-protein coupled receptor encoded by the OPRM1 gene through which opioid drugs produce analgesia as well as OIH [ 97 ]. It is expressed at high levels in primary afferents, the spinal dorsal horn and in the aforementioned brainstem structures [ 98 ].…”

“…These alterations in MOR signaling pathways include the switching of MOR coupling from an inhibitory G-protein to a stimulatory G-protein, abnormally promoting phosphorylation and intracellular activity dependent on PKA-dependent pathways, which favor neurotransmission in the afferent neurons of the nociceptive pathways [ 44 , 99 , 100 ]. The inhibitory-to-stimulatory modification in MOR signaling has also been demonstrated in the DRt, in experimental models of OIH due to chronic morphine treatment while DRt inactivation with targeted lidocaine injections successfully reversed OIH experimentally [ 97 ].…”

Monoaminergic and Opioidergic Modulation of Brainstem Circuits: New Insights Into the Clinical Challenges of Pain Treatment?

“…Tolerance to opioids leads to increasing doses of opioids, which is critical as this can lead to opioid-induced hyperalgesia [ 145 ]. Chronic morphine treatment induces a shift of MOR signaling from inhibitory to excitatory at the DRt, enhancing DF from the DRt [ 146 ]. These findings indicate that the cumulative effects of neuropathic pain and opioid drugs on MOR are counterproductive.…”