Opioid drugs are a first-line treatment for severe
acute pain and other
chronic pain conditions, but long-term
opioid drug use produces
opioid-induced
hyperalgesia (OIH). Co-administration of
cannabinoids with
opioid receptor agonists produce anti-nociceptive synergy, but
cannabinoid receptor agonists may also produce undesirable side effects. Therefore, positive allosteric modulators (PAM) of
cannabinoid type-1 receptors (CB1R) may provide an option reducing
pain and/or enhancing the anti-hyperalgesic effects of
opioids without the side effects, tolerance, and dependence observed with the use of
ligands that target the orthosteric binding sites. This study tested
GAT211, a PAM of
cannabinoid type-1 receptors (CB1R), for its ability to enhance the anti-hyperalgesic effects of the
mu-opioid receptor (MOR) agonist
DAMGO in rats treated chronically with
morphine (or saline) and tested during withdrawal. We tested the effects of intra-periaqueductal gray (PAG)
injections of (1)
DAMGO, (2)
GAT211, or (3)
DAMGO +
GAT211 on thermal nociception in chronic
morphine-treated rats that were hyperalgesic and also in saline-treated control rats. We used slice electrophysiology to test the effects of
DAMGO/
GAT211 bath application on synaptic transmission in the vlPAG. Intra-PAG
DAMGO infusions dose-dependently reversed chronic
morphine-induced
hyperalgesia, but intra-PAG
GAT211 did not alter nociception at the doses we tested. When co-administered into the PAG,
GAT211 antagonized the anti-nociceptive effects of
DAMGO in
morphine-withdrawn rats.
DAMGO suppressed synaptic inhibition in the vlPAG of brain slices taken from saline- and
morphine-treated rats, and
GAT211 attenuated
DAMGO-induced suppression of synaptic inhibition in vlPAG neurons via actions at CB1R. These findings show that positive allosteric modulation of CB1R antagonizes the behavioral and cellular effects of a MOR agonist in the PAG of rats.