Effects of repeated treatment with monoamine-transporter-inhibitor antidepressants on pain-related depression of intracranial self-stimulation in rats

Abstract

Synaptic neurotransmission with dopamine (DA), norepinephrine (NE), and serotonin (5-HT) is terminated primarily by reuptake into the presynaptic terminal via the DA, NE, and 5-HT transporters (DAT/NET/SERT, respectively). Monoamine transporter inhibitors constitute one class of drugs used to treat pain, and emergence of analgesic effects by these compounds often requires repeated treatment for days or weeks. The present study compared antinociceptive effects produced by repeated treatment with monoamine transporter inhibitors in a preclinical assay of pain-related depression of positively reinforced operant responding. Adult male Sprague-Dawley rats equipped with microelectrodes targeting a brain-reward area responded for pulses of electrical brain stimulation in an intracranial self-stimulation (ICSS) procedure.Intraperitoneal injection of dilute lactic acid served as a noxious stimulus that repeatedly depressed ICSS and also produced weight loss during 7 days of repeated acid administration.Both acid-induced ICSS depression and weight loss were blocked by repeated pretreatment with the nonsteroidal anti-inflammatory drug ketorolac (a positive control) but not by the kappa opioid receptor agonist U69,593 (a negative control). Like ketorolac, the DAT/NET inhibitor bupropion fully blocked acid-induced ICSS depression and weight loss throughout all 7 days of treatment. Conversely, the NET-selective inhibitor nortriptyline and SERT-selective inhibitor citalopram produced antinociception only after several days of repeated treatment, and weight loss was attenuated by citalopram but not by nortriptyline. These results support effectiveness of bupropion to alleviate signs of pain-related behavioral depression in rats and further suggest that nortriptyline and citalopram produce a more gradual onset of antinociception during repeated treatment.

Resistance of Food-Maintained Operant Responding to Mechanical Punishment in Rats: Further Evidence for Weak “Affective/Motivational Pain” in Rat Models of Inflammatory and Neuropathic Pain

“…Second, inflammation and neuropathy in rodents have also been reported to promote dynorphin signaling and KOR activation in the mesolimbic dopamine system, and this enhanced KOR signaling has been implicated in some signs of pain-related behavioral depression (Liu et al, 2019;Meade et al, 2020). We have not found evidence for this type of pain-related activation of KOR signaling in previous studies using both acute and chronic pain manipulations (Leitl et al, 2014a;Leitl et al, 2014b;Negus et al, 2015;Bagdas et al, 2016;Legakis et al, 2020), and the present study is consistent with our own previous findings. Thus, CFA and paclitaxel treatment produced only transient and/or weak evidence for depression of operant responding, so there was little evidence to suggest a KORmediated depressant effect in this study.…”

Lack of effect of different pain-related manipulations on opioid self-administration, reinstatement of opioid seeking, and opioid choice in rats

“…To address these limitations, in Experiment 2, we modified the experimental design and increased the number of pairings between pain exposure and opioid self-administration. We used lactic acid as a noxious stimulus because it can be administered repeatedly without developing tolerance to its pain-related decrease on operant responding (Legakis et al 2020; Miller et al 2015).…”

“…Therefore, in Experiment 2, we used a different acute pain-related manipulation, daily i.p. injections of lactic acid, which does not require anesthesia (Negus 2013; Pereira Do Carmo et al 2009) and for which tolerance does not develop after repeated exposure (Legakis et al 2020; Miller et al 2015). Furthermore, because the context manipulation in Experiment 1 was ineffective, we simplified the experimental design and eliminated the context in which a noxious stimulus was absent.…”

Does urinary metabolite signature act as a biomarker of post-stroke depression?

“…Furthermore, DA is converted into noradrenaline (NA) by DA hydroxylase. Numerous studies (72)(73)(74)(75)(76)(77)(78)(79)(80)(81)(82)(83) confirmed that the dysfunction of monoamine neurotransmitters such as NE, DA, and 5-HT plays a crucial part in the pathogenesis of depressive disorder. Elevated DA, L-DOPA, and vanillylmandelic acid (VMA) levels were found in the hippocampus of CSDSinduced model mice (84,85).…”