Chronic pregabalin inhibits synaptic transmission between rat dorsal root ganglion and dorsal horn neurons in culture

Abstract

In this study, we have examined the properties of synaptic transmission between dorsal root ganglion (DRG) and dorsal horn (DH) neurons, placed in co-culture. We also examined the effect of the anti-hyperalgesic gabapentinoid drug pregabalin (PGB) at this pharmacologically relevant synapse. The main method used was electrophysiological recording of excitatory post synaptic currents (EPSCs) in DH neurons. Synaptic transmission between DRG and DH neurons was stimulated by capsaicin, which activates transient receptor potential vanilloid-1 (TRPV1) receptors on small diameter DRG neurons. Capsaicin (1 μM) application increased the frequency of EPSCs recorded in DH neurons in DRG-DH co-cultures, by about 3-fold, but had no effect on other measured properties of the EPSCs. There was also no effect of capsaicin in the absence of co-cultured DRGs. Application of PGB (100 μM) for 40–48 h caused a reduction in the capsaicin-induced increase in EPSC frequency by 57%. In contrast, brief preincubation of PGB had no significant effect on the capsaicin-induced increase in EPSC frequency. In conclusion, this study shows that PGB applied for 40–48 h, but not acute application inhibits excitatory synaptic transmission at DRG-DH synapses, in response to nociceptive stimulation, most likely by a presynaptic effect on neurotransmitter release from DRG presynaptic terminals.

Systemic pregabalin attenuates facial hypersensitivity and noxious stimulus-evoked release of glutamate in medullary dorsal horn in a rodent model of trigeminal neuropathic pain

“…Like gabapentin, pregabalin is an adjuvant antiepileptic drug that is a structural analog of GABA, but has no action at GABA receptors, and does not affect GABA synthesis (Dolphin, 2012; Hendrich et al, 2012; Li et al, 2011). Pregabalin has been shown to modulate the release of several neurotransmitters by selectively binding to the α 2 δ auxiliary subunit of calcium channels to reduce the influx of Ca 2+ ions, thereby reducing the release of glutamate, norepinephrine and substance P (Li et al, 2011; Dolphin, 2012).…”

“…There is an increase in α 2 δ−1 at presynaptic terminals in the superficial dorsal horn in neuropathic rats that have allodynia and hyperalgesia, which is inhibited by pregabalin (Li et al, 2011). Pregabalin also inhibits the trafficking of calcium channels in dorsal root ganglion cells (Hoppa et al, 2012), and pregabalin binding at α 2 δ channels reduces synaptic transmission between rat dorsal root ganglion and dorsal horn neurons in culture (Hendrich et al, 2012). …”

“…In vitro investigations have shown that pregabalin reduces transmission between dorsal root ganglion and the spinal cord dorsal horn neurons in cultured slices (Hendrich et al, 2012). In vivo studies have also shown that pregabalin attenuates glutamate release in the spinal cord dorsal horn of animals with neuropathic pain (Kumar et al, 2010).…”

Etiology and Pharmacology of Neuropathic Pain

“…By contrast, slowly developing actions of gabapentinoids seen in uninjured dorsal horn neurons in vitro (Moore et al, 2002;Hendrich et al, 2012;Biggs et al, 2014) may reflect interruption of trafficking of a 2 d subunits from cell bodies to nerve terminals (Alles and Smith, 2016). The concept of actions of gabapentinoids on injured nerves and slower actions on uninjured nerves is illustrated schematically in Fig.…”

Modulation of nociceptive ion channels and receptors via protein-protein interactions: implications for pain relief

“…inhibition of neuropathic pain-induced membrane trafficking of the 2δ1-subunit and concomitantly prevention of excessive HVA channel function. 78,79 In contrast to the inhibitory action of pregabalin, collapsin response mediator protein 2 (CRMP-2) was reported to bind to HVA N-type calcium channels (Cav2.2) resulting in increased surface expression as well as calcium currents in hippocampal and sensory neurons. [80][81][82][83] Further work established the notion that CRMP-2 expression levels allow the control of Cav2.2 function, nociceptor excitability and transmitter release.…”