Effects of Repeated Treatment with Monoamine-Transporter-Inhibitor Antidepressants on Pain-Related Depression of Intracranial Self-Stimulation in Rats

Abstract

<jats:title>ABSTRACT</jats:title><jats:p>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.</jats:p>

Effects of Repeated Treatment with the Monoacylglycerol Lipase Inhibitor MJN110 on Pain-Related Depression of Nesting and Cannabinoid 1 Receptor Function in Male and Female Mice

“…The present results agree with our previous finding in rats that repeated daily administration of IP acid can produce both (a) consistent daily episodes of pain-related behavioral depression and (b) weight loss as a potential indicator of depressed feeding (Miller et al, 2015;Legakis et al, 2020). In those previous studies, repeated IP acid decreased a positively reinforced operant-conditioned behavior in rats.…”

“…For example, we recently reported that intraperitoneal administration of dilute lactic acid (IP acid) served as an acute visceral noxious stimulus to depress nesting behavior in mice, and this pain-related nesting depression could be significantly but only partially alleviated by MJN110 doses of 0.32-3.2 mg/kg (Diester et al, 2021a;Diester et al, 2021b). Daily IP acid injection produces repeated episodes of behavioral depression and permits assessment of effects produced by repeated drug treatments, and we have shown in rats that morphine-induced alleviation of pain-depressed behavior is resistant to tolerance while effects of some antidepressants increase with repeated administration (Miller et al, 2015;Legakis et al, 2020). The present study used this approach to evaluate antinociception produced by repeated 1.0 mg/kg MJN110 treatment in mice treated with repeated IP acid.…”

“…In addition to these effects on nesting, MJN110 treatment also alleviated IP acid-induced weight loss. This MJN110 effect in mice resembles the blockade of IP acid-induced weight loss by the nonsteroidal anti-inflammatory drug ketorolac in rats (Legakis et al, 2020); however, two findings challenge the conclusion that MJN110 effects on body weight reflect antinociception.…”

“…Weight Data. Repeated IP acid may decrease body weight as a surrogate measure for pain-related and analgesic-reversible depression of feeding behavior (Stevenson et al, 2006;Legakis et al, 2020). Accordingly, weights for each subject were collected daily immediately prior to MJN110 or vehicle administration.…”