Locomotor and anti-immobility effects of buprenorphine in combination with the opioid receptor modulator samidorphan in rats

Abstract

Modulation of the opioid system has re-emerged as a potential therapeutic avenue for treating depression, with efficacy of a fixed-dose combination of buprenorphine (BUP), a partial µ-opioid receptor (MOR) agonist and κ-opioid receptor (KOR) antagonist, and samidorphan (SAM), a potent MOR antagonist, as an adjuvant treatment in patients with major depressive disorder (MDD). To advance understanding of the mechanism of action underlying this combination, we examined BUP, SAM and their combination in a series of rat behavioural assays. We examined effects on locomotor activity in Sprague Dawley (SD) rats over an extended period of time in a home-cage tracking system, and behavioural despair (immobility) in the forced swim test (FST), a commonly-used test to study antidepressants, in SD and Wistar-Kyoto (WKY) rats. Strain differences in opioid receptor and prepropeptide mRNA expression in the brain (prefrontal cortex, amygdala, hippocampus and striatum) were examined using qRT-PCR. BUP produced locomotor hyperactivity in SD rats from 2-6 h following administration, which was attenuated by SAM. In SD rats, a low, but not a high, dose of SAM in combination with BUP counteracted swim-stress induced immobility. This effect was not seen with BUP alone. In contrast, BUP alone reduced immobility in WKY rats, and this effect was enhanced by a low, but not high, dose of SAM. In WKY rats, MOR mRNA expression was higher in the hippocampus and lower in the striatum vs. SD rats. KOR mRNA expression was higher in the amygdala and nociceptin receptor (NOP) mRNA expression was lower in the hippocampus vs. SD rats. Differences in opioid receptor expression may account for the differential behavioural profile of WKY and SD rats. In summary, administration of BUP, a MOR receptor agonist together with a MOR opioidreceptor antagonist, SAM, reduces behavioural despair in animal models traditionally used to study effects of antidepressants.

Chronic administration of buprenorphine in combination with samidorphan produces sustained effects in olfactory bulbectomised rats and Wistar-Kyoto rats

“…Buprenorphine alone, but not the buprenorphine-samidorphan combination, increases locomotor activity three hours after final dosing in repeatedly-treated Wistar-Kyoto rats. Similar time-dependent locomotor effects were also observed following single dosing in Wistar-Kyoto rats (Smith et al, 2019) and in C57BL mice (Falcon et al, 2015), and after single and repeated treatment in Sprague-Dawley rats (Burke et al, 2019). Effects of buprenorphine on locomotor activity confound its apparent anti-immobility effect, and may relate to an activation of the mu-opioid system.…”

“…Buprenorphine also increased locomotor activity in Wistar-Kyoto rats. As acute and subacute buprenorphine and the buprenorphine-samidorphan combination were effective in the forced swim test (Burke et al, 2019; Smith et al, 2019), the results from the current study suggest that these effects are maintained with chronic treatment.…”

“…In Wistar-Kyoto rats, exaggerated forced-swim immobility is accompanied by increased kappa-opioid receptor and dynorphin A expression (Carr et al, 2010). Our recent work shows that Wistar-Kyoto rats have higher mu-opioid receptor and lower nociceptin receptor mRNA expression in the hippocampus; lower mu-opioid receptor mRNA in the striatum; and higher kappa-opioid mRNA expression in the amygdala when compared to Sprague-Dawley rats (Burke et al, 2019). A single treatment with buprenorphine (Browne et al, 2015) or the kappa receptor antagonist nor-BNI (nor-Binaltorphimine) (Carr et al, 2010) significantly reduced forced-swim immobility in Wistar-Kyoto rats.…”

“…Evidence from some (but not all) clinical studies suggests the combination of buprenorphine with samidorphan reduces depressive symptoms in patients with MDD and an inadequate response to their current therapy, when administered as an adjunct treatment to monoaminergic antidepressants (Ehrich et al, 2015;Fava et al, 2018;Peckham, De La Cruz, & Dufresne, 2018). In non-clinical studies, acute and subacute administration of buprenorphine with samidorphan induces behavioural changes indicative of antidepressant-like activity (Burke et al, 2019;Smith et al, 2019). It is unknown if the buprenorphine and samidorphan combination induces similar behavioural changes after chronic treatment in well-validated animal models.…”

Buprenorphine: prospective novel therapy for depression and PTSD

“…Samidorphan attenuated buprenorphine-induced increase in extracellular levels of serotonin and dopamine in the medial prefrontal cortex and nucleus accumbens shell (Smith et al, 2019). Additionally, samidorphan blocked buprenorphine-induced hyperactivity, a behavioral response to increased striatal extracellular dopamine (Burke et al, 2019; Smith et al, 2019). Opioid-induced increase in extracellular dopamine makes them reinforcing, and renders them liable for abuse and addiction (Merrer, Becker, Befort, & Kieffer, 2009; Shippenberg & Elmer, 1998).…”