Repeated morphine treatment alters cannabinoid modulation of GABAergic synaptic transmission within the rat periaqueductal grey.
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.
Midbrain PAG slices were prepared from untreated rats, and rats that had undergone repeated morphine, or saline pre-treatment. Whole cell voltage-clamp recordings were made from neurons within the ventrolateral PAG.
In slices from untreated animals, the cannabinoid receptor agonist WIN55212 and the μ-opioid 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.
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Opioid; cannabinoid; periaqueductal grey; synaptic transmission; tolerance
- [PubMed – as supplied by publisher]