We observed that co-application of Pn3a and µ-OR agonist DAMGO results in enhanced HVA- I Ca inhibition in DRG neurons whereas co-application of Pn3a with the OR antagonist naloxone does not, underscoring HVA channels as shared targets of Pn3a and opioids. As a major DRG I Ca component, Ca v2.2 inhibition by Pn3a ( IC 50 = 3.71 ± 0.21 µM) arises from an 18 mV hyperpolarizing shift in the voltage dependence of inactivation.
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Using whole-cell patch clamp recording, we found that Pn3a (10 µM) inhibits ∼55% of rat DRG neuron HVA- I Ca and 60–80% of Ca v1.2, Ca v1.3, Ca v2.1, and Ca v2.2 mediated currents in HEK293 cells, with no inhibition of Ca v2.3. These channels mediate the high voltage-activated (HVA) calcium currents ( I Ca) that orchestrate synaptic transmission in nociceptive dorsal root ganglion (DRG) neurons and are fine-tuned by opioid receptor (OR) activity. Na v channels are structurally related to voltage-gated calcium (Ca v) channels, Ca v1 and Ca v2. 3Electrophysiology Facility for Cell Phenotyping and Drug Discovery, IHMRI, Wollongong, NSW, Australiaĭespite potently inhibiting the nociceptive voltage-gated sodium (Na v) channel, Na v1.7, µ-theraphotoxin Pn3a is antinociceptive only upon co-administration with sub-therapeutic opioid agonists, or by itself at doses >3,000-fold greater than its Na v1.7 IC 50 by a yet undefined mechanism.2Discipline of Pharmacology, University of Sydney, Sydney, NSW, Australia.1Illawarra Health and Medical Research Institute (IHMRI), University of Wollongong, Wollongong, NSW, Australia.
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