Nortriptyline Enhances Morphine-Conditioned Place Preference in Neuropathic Rats: Role of the Central Noradrenergic System

Abstract

BACKGROUND Combination drug therapy is commonly used to treat chronic pain conditions such as neuropathic pain, and antidepressant is often used together with opioid analgesics. While rewarding is an intrinsic property of opioid analgesics, it is unknown whether the use of antidepressant would influence opioid reward, which may contribute to opioid addiction. In the present study, we examined whether nortriptyline (a tricyclic antidepressant and a first-line medication for neuropathic pain) would enhance the morphine rewarding property in both naïve and chronic constriction sciatic nerve injury (CCI) rats. METHODS The rewarding effect of these drugs was assessed using conditioned place preference (CPP). The real-time PCR, western blot and ELISA analysis were used to investigate the function of central noradrenergic system. RESULTS In naïve rats, co-administration of nortriptyline with morphine did not change the acquisition of morphine-induced CPP. However, nortriptyline enhanced the acquisition, delayed the extinction, and augmented the reinstatement of morphine-induced CPP in CCI rats. In CCI rats treated with both nortriptyline and morphine, the expression of α2A adrenergic receptors, norepinephrine transporter, and tyrosine hydroxylase was markedly decreased in the locus coeruleus, whereas the norepinephrine concentration in the nucleus accumbens was remarkably increased. CONCLUSIONS These results demonstrate that nortriptyline enhanced morphine reward when both drugs were used to treat neuropathic pain in rats and that this behavioral phenotype is likely to be mediated by upregulation of the central noradrenergic system. These findings may have implications in opioid therapy commonly used for chronic pain management.

Identification of discrete, intermingled hypocretin neuronal populations

“…Although the LC and TMN are often described as wakefulness/arousal populations and the VTA and NAc are often described as reward populations, wakefulness and reward-seeking behaviors are linked, and these downstream nuclei can indeed regulate behaviors much more broadly. For example, activity in the LC-norepinephrine system is sufficient to cause cue-induced reinstatement of reward seeking (Al-Hasani, McCall, Foshage, & Bruchas, 2013; Mi et al, 2017; Shaham, Highfield, Delfs, Leung, & Stewart, 2000). Likewise, stimulants that enhance VTA activity and dopaminergic tone promote wakefulness (Boutrel & Koob, 2004), and activation of the VTA has recently been shown to increase arousal during the presentation of salient and rewarding stimuli (Eban-Rothschild, Rothschild, Giardino, Jones, & de Lecea, 2016).…”

Crucial involvement of catecholamine neurotransmission in postoperative nausea and vomiting: Whole‐transcriptome profiling in the rat nucleus of the solitary tract

“…Recent experiments have demonstrated a correlation between the opioid‐induced reward and the enzymes that occur in catecholamine biosynthesis, such as TH, in opioid addiction‐related brain areas of rodents. In both the hippocampus and the locus ceruleus, TH expression is significantly increased after chronic morphine treatment 32–34 . In the nucleus accumbens and the ventral tegmental area, TH expression is significantly decreased 35–37 .…”

Morphine Exacerbates Postfracture Nociceptive Sensitization, Functional Impairment, and Microglial Activation in Mice

“…Considering the US opioid epidemic, recently declared a public health emergency, the relationship between postoperative/traumatic pain and addiction should be better elucidated. A surprisingly small number of reports have provided evidence that opioids administered in models of persistent pain can strengthen place preference for morphine, and reduce the extinction of these behaviors [54,55]. Surgical models have not been well explored using place preference paradigms.…”