For an affliction
that debilitates an estimated 50 million adults
in the United States, the current chronic pain management approaches
are inadequate. The Centers for Disease Control and Prevention have
called for a minimization in opioid prescription and use for chronic
pain conditions, and thus, it is imperative to discover alternative
non-opioid based strategies. For the realization of this call, a library
of natural products was screened in search of pharmacological inhibitors
of both voltage-gated calcium channels and voltage-gated sodium channels,
which are excellent targets due to their well-established roles in
nociceptive pathways. We discovered (−)-hardwickiic acid ((−)-HDA)
and hautriwaic acid (HTA) isolated from plants, Croton californicus and Eremocarpus setigerus, respectively, inhibited
tetrodotoxin-sensitive sodium, but not calcium or potassium, channels
in small diameter, presumptively nociceptive, dorsal root ganglion
(DRG) neurons. Failure to inhibit spontaneous postsynaptic excitatory
currents indicated a preferential targeting of voltage-gated sodium
channels over voltage-gated calcium channels by these extracts. Neither
compound was a ligand at opioid receptors. Finally, we identified
the potential of both (−)-HDA and HTA to reverse chronic pain
behavior in preclinical rat models of HIV-sensory neuropathy, and
for (−)-HDA specifically, in chemotherapy-induced peripheral
neuropathy. Our results illustrate the therapeutic potential for (−)-HDA
and HTA for chronic pain management and could represent a scaffold,
that, if optimized by structure–activity relationship studies,
may yield novel specific sodium channel antagonists for pain relief.