A R Wilson-Poe1, B K Lau, C W Vaughan. 1. Pain Management Research Institute, Kolling Institute for Medical Research, Northern Clinical School, The University of Sydney, St Leonards, NSW, Australia.
Abstract
BACKGROUND AND PURPOSE: Cannabinoids and opioids produce antinociception by modulating GABAergic synaptic transmission in a descending analgesic pathway from the midbrain periaqueductal grey (PAG). While chronic opioid treatment produces opioid tolerance, it has recently been shown to enhance cannabinoid-induced antinociception within the PAG. This study examined the effect of repeated opioid treatment on opioid and cannabinoid presynaptic modulation of GABAergic synaptic transmission in PAG. EXPERIMENTAL APPROACH: Midbrain PAG slices were prepared from untreated rats, and rats that had undergone repeated morphine or saline pretreatment. Whole-cell voltage-clamp recordings were made from neurons within the ventrolateral PAG. KEY RESULTS: In slices from untreated animals, the cannabinoid receptor agonist WIN55212 and the μ receptor agonist DAMGO inhibited electrically evoked GABAA receptor-mediated inhibitory postsynaptic currents (IPSCs) IPSCs in PAG neurons, with IC50 s of 30 and 100 nM respectively. The inhibition of evoked IPSCs produced by WIN55212 (30 nM) and DAMGO (100 nM) was similar in PAG neurons from morphine- and saline-treated animals. The cannabinoid CB1 receptor antagonist AM251 increased the frequency of spontaneous miniature IPSCs in PAG neurons from repeated morphine-, but not saline-treated animals. DAMGO inhibition of evoked IPSCs was enhanced in the presence of AM251 in morphine-, but not saline-treated animals. CONCLUSIONS AND IMPLICATIONS: These results indicate that the efficiency of agonist-induced inhibition of GABAergic synaptic transmission is enhanced by morphine treatment, although this is dampened by endocannabinoid-mediated tonic inhibition. Thus, endocannabinoid modulation of synaptic transmission could provide an alternative analgesic approach in a morphine-tolerant state. LINKED ARTICLES: This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2.
BACKGROUND AND PURPOSE: Cannabinoids and opioids produce antinociception by modulating GABAergic synaptic transmission in a descending analgesic pathway from the midbrain periaqueductal grey (PAG). While chronic opioid treatment produces opioid tolerance, it has recently been shown to enhance cannabinoid-induced antinociception within the PAG. This study examined the effect of repeated opioid treatment on opioid and cannabinoid presynaptic modulation of GABAergic synaptic transmission in PAG. EXPERIMENTAL APPROACH: Midbrain PAG slices were prepared from untreated rats, and rats that had undergone repeated morphine or saline pretreatment. Whole-cell voltage-clamp recordings were made from neurons within the ventrolateral PAG. KEY RESULTS: In slices from untreated animals, the cannabinoid receptor agonist WIN55212 and the μ receptor agonist DAMGO inhibited electrically evoked GABAA receptor-mediated inhibitory postsynaptic currents (IPSCs) IPSCs in PAG neurons, with IC50 s of 30 and 100 nM respectively. The inhibition of evoked IPSCs produced by WIN55212 (30 nM) and DAMGO (100 nM) was similar in PAG neurons from morphine- and saline-treated animals. The cannabinoidCB1 receptor antagonist AM251 increased the frequency of spontaneous miniature IPSCs in PAG neurons from repeated morphine-, but not saline-treated animals. DAMGO inhibition of evoked IPSCs was enhanced in the presence of AM251 in morphine-, but not saline-treated animals. CONCLUSIONS AND IMPLICATIONS: These results indicate that the efficiency of agonist-induced inhibition of GABAergic synaptic transmission is enhanced by morphine treatment, although this is dampened by endocannabinoid-mediated tonic inhibition. Thus, endocannabinoid modulation of synaptic transmission could provide an alternative analgesic approach in a morphine-tolerant state. LINKED ARTICLES: This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2.
Authors: Leon W Fyfe; Daniel R Cleary; Tara A Macey; Michael M Morgan; Susan L Ingram Journal: J Pharmacol Exp Ther Date: 2010-08-25 Impact factor: 4.030
Authors: Jenny L Wilkerson; Micah J Niphakis; Travis W Grim; Mohammed A Mustafa; Rehab A Abdullah; Justin L Poklis; William L Dewey; Hamid Akbarali; Matthew L Banks; Laura E Wise; Benjamin F Cravatt; Aron H Lichtman Journal: J Pharmacol Exp Ther Date: 2016-01-20 Impact factor: 4.030