Cholecystokinin Exerts an Effect via the Endocannabinoid System to Inhibit GABAergic Transmission in Midbrain Periaqueductal Gray

Abstract

Cholecystokinin modulates pain and anxiety via its functions within brain regions such as the midbrain periaqueductal gray (PAG). The aim of this study was to examine the cellular actions of cholecystokinin on PAG neurons. Whole-cell patch clamp recordings were made from rat midbrain PAG slices in vitro to examine the postsynaptic effects of cholecystokinin and its effects on synaptic transmission. Sulfated cholecystokinin-(26-33) (CCK-S, 100-300 nM), but not non-sulfated cholecystokinin-(26-33) (CCK-NS, 100-300 nM) produced an inward current in a sub-population of opioid sensitive and insensitive PAG neurons, which did not reverse over a range of membrane potentials. The CCK-S-induced current was abolished by the CCK1 selective antagonist devazepide (100 nM), but not by the CCK2 selective antagonists CI988 (100 nM, 1 mM) and LY225910 (1 mM). CCK-S, but not CCK-NS produced a reduction in the amplitude of evoked GABA A -mediated inhibitory postsynaptic currents (IPSCs) and an increase in the evoked IPSC paired-pulse ratio. By contrast, CCK-S had little effect on the rate and amplitude of TTX-resistant miniature IPSCs under basal conditions and when external K + was elevated. The CCK-S-induced inhibition of evoked IPSCs was abolished by the cannabinoid CB1 receptor antagonist AM251 (3 mM), the mGluR5 antagonist MPEP (10 mM) and the 1, 2-diacylglycerol lipase (DAGLa) inhibitor tetrahydrolipstatin (10 mM). In addition, CCK-S produced an increase in the rate of spontaneous non-NMDA-mediated, TTX-dependent excitatory postsynaptic currents (EPSCs). These results suggest that cholecystokinin produces direct neuronal depolarisation via CCK1 receptors and inhibits GABAergic synaptic transmission via action potential-dependent release of glutamate and mGluR5-induced endocannabinoid signaling. Thus, cholecystokinin has cellular actions within the PAG that can both oppose and reinforce opioid and cannabinoid modulation of pain and anxiety within this brain structure.

Genotype-dependent responsivity to inflammatory pain: A role for TRPV1 in the periaqueductal grey

“…CCK stimulates descending facilitation of pain suggesting a pro-nociceptive role (Lovick, 2008). GABA A receptor-mediated inhibitory postsynaptic currents in the dorsal root ganglia (Ma et al, 2006) and PAG (Mitchell et al, 2011) (Andre et al, 2005). Overall CCK is involved in hyperalgesia associated with negative affective state, but the exact mechanisms are yet to be elucidated.…”

The Effects of Orexin A and B on Two Forms of Immobility Responses and on Analgesia

“…Therefore may produce antinociception by activating postsynaptic OXR1, stimulating synthesis of 2-arachidonoylglycerol, an endocannabinoid through a G q -protein-mediated 1,2diacylglycerol lipase (PLC-DAGCL␣) enzymatic cascade [31]. Same mechanism of action has been proposed as analgesic to sulfated cholecystokinin in PAG by another in vitro study [32] and via metabotropic glutamate receptor mediated endocannabinoid retrograde disinhibition for capsaicin [33]. However, to our knowledge this action mechanism has not been demonstrated for orexin B yet.…”

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

“…One of these systems is the cholecystokinin (CCK) system that has been studied especially in relation to analgesic effects of m-opioid receptor stimulation (reviewed in Wiesenfeld-Hallin et al, 1999). For example, CCK peptides, G protein-coupled CCK 1 , and CCK 2 receptors show complex expression patterns and interact with a number of neurotransmitter/ modulator mechanisms to both oppose and reinforce opioid-induced analgesia and anxiolysis within the PAG (Mitchell et al, 2011). CCK is also strongly expressed in the VTA (Ballaz et al, 2013) and can influence drug-induced reward processes.…”