Published in the Proceedings of the National Academy of Sciences, the research explores how these cannabinoids interact with a protein called Nav1.8 found in the cell membrane of sensory neurons in the spine and responsible for the repetitive firing of pain-transmitting neurons.
“These findings open new avenues for the development of cannabinoid-based therapies,” Mohammad-Reza Ghovanloo, lead author of the study and an associate research scientist in the Department of Neurology at Yale School of Medicine, shared in a statement. “Our results show that CBG in particular has the strongest potential to provide effective pain relief without the risks associated with traditional treatments.”
The researchers were supported by grants from the U.S. Department of Veterans Affairs Rehabilitation Research and Development Service, the Canadian Institutes of Health Research (CIHR) and the National Institutes of Health.
Cannabinoids and chronic pain management
According to the Centers for Disease Control, chronic pain affects nearly 25% of Americans, resulting in an estimated annual $560 to $635 billion in medical care and disability costs.
In this context, cannabis and its compounds have gained traction as part of a multifaceted approach to pain management, particularly considering the persistent U.S. opioid epidemic—a public health crisis characterized by poorly managed pain, opioid addiction and drug overdose.
“Pharmacological studies have shown that cannabinoid compounds exert a range of effects on multiple ion channels and receptors, influenced by local membrane environments (e.g., membrane potential) and protein expression patterns,” the researchers noted. “These interactions have shown potential for the treatment of epilepsy, pain and chemotherapy-induced neuropathy.”
They propose that both endocannabinoid (CB)-dependent and CB-independent pathways (acting through other targets like Nav channels) contribute to cannabinoid-mediated anti-pain effects. Beyond CBD and delta-9-THC, CBG and CBN have both demonstrated inhibitory effects on these receptors and pathways.
Targeting Nav channels
The researchers noted that the psychological/emotional component of pain is primarily dependent on neuronal circuits within the central nervous system, while the nociceptive component (the perception or sensation of pain) refers to the neural encoding of impending or actual tissue damage, which occurs in the peripheral nervous system.
Much of the drug discovery effort has focused on targets within the nociceptive pathways, as modulation of these targets is more biologically quantifiable and less subjective, presenting the opportunity to target peripheral channels as strategy to develop nonaddictive therapies.
“This has led to a focus on key mediators of nociceptor excitability, where voltage-gated sodium (Nav) channels in the peripheral nervous system—Nav1.7, Nav1.8 and Nav1.9—play crucial roles in pain signaling,” the researchers wrote. “Among these, Nav1.8 has shown promise due to its rapid recovery from inactivation and role in repetitive firing, with recent clinical studies providing proof-of-principal that blocking of Nav1.8 can reduce pain in humans.”
To evaluate effects, the Yale study measured the electrical current in rodent sensory neurons and how it changed when CBD, CBG and CBN were introduced. All reduced the cells’ electrical current amplitudes associated with Nav1.8, with CBG showing the strongest inhibitory action.
“Targeting voltage-gated sodium (Nav) channels in sensory neurons, particularly Nav1.8, represents a promising therapeutic approach,” the researchers concluded, calling for further in vivo studies. “Our work demonstrates that nonpsychotomimetic cannabinoids, including cannabidiol (CBD), cannabigerol (CBG) and cannabinol (CBN), effectively inhibit Nav1.8.”
They attributed CBG’s more pronounced effects to its potent ability to curb the excitability of the peripheral dorsal root ganglion neuron.
Source: Proceedings of the National Academy of Sciences. doi: 10.1073/pnas.2416886122. “Nav1.8, an analgesic target for nonpsychotomimetic phytocannabinoids”. Authors: Mohammad-Reza Ghovanloo et al.
