Chronic pain affects approximately one in five adults, significantly negatively impacting quality of life and leading to severe socioeconomic consequences. In fact, when all pain conditions are considered, chronic pain is the leading cause of disability worldwide. Unfortunately, current treatments for chronic pain are often suboptimal due to poor efficacy and tolerability. The molecular causes of chronic pain are not fully understood, but increased excitability of nociceptors and the central pain pathways to which they project are important factors contributing to this state of pain sensitization.
Polyamines are key regulatory metabolites that play important roles in transcription, translation, cell signaling, and autophagy. They are implicated in a variety of neurological disorders, including stroke, epilepsy, and neurodegenerative diseases, and can regulate neuronal excitability through interactions with ion channels. Polyamines are also implicated in pain, with altered levels in persistent pain states in humans and their ability to modulate pain behaviors in animal models. However, the mechanisms of polyamine transport in the nervous system remain largely unknown.
Researchers from the University of Oxford recently published a research paper titled "SLC45A4 is a pain gene encoding a neuronal polyamine transporter" in the leading international academic journal Nature. The study confirmed that SLC45A4, a pain gene encoding a neuronal polyamine transporter, is strongly associated with the risk of chronic pain in humans. Mice lacking the SLC45A4 protein exhibit normal mechanical sensitivity but reduced sensitivity to persistent pain induced by noxious heat and analgesics. This discovery provides a new target for the treatment of chronic pain.
Figure 1. SLC45A4 is a polyamine transporter with a plug domain. (Middleton S J, et al., 2025)
Endogenous metabolites, including putrescine (Put), spermine (Spm), and spermidine (Spd), are thought to be involved in chronic pain. These ubiquitous polycationic alkylamines play important roles in nucleic acid synthesis and stability, cell signaling (including stress responses), and growth, but they also regulate ion channel function. Serum and tissue polyamine levels are elevated in painful conditions such as inflammation and rheumatoid arthritis. Injection of polyamines into the plantar or intrathecal space of the spinal cord in rodents induces pain behaviors, while inhibition of their synthesis reduces inflammatory pain.
However, the specific direction or site of action of polyamines remains unclear, as does how to target them through therapeutic intervention optimally. The effects of polyamines on ion channels are highly dependent on their location (intracellular or extracellular), making understanding the trafficking of these metabolites crucial for determining their effects on neuronal function. Furthermore, excessive polyamines are toxic, and cells must tightly control their homeostasis to maintain normal function; however, how this is achieved remains unclear.
To date, researchers have only identified the intracellular polyamine transport system, including the lysosomal polyamine transporter ATP13A2, which is associated with Parkinson's disease, and the vesicular polyamine transporters ATP13A3 and SLC18B1. The components of the plasma membrane polyamine transport system remain largely unknown.
In this new study, the research team discovered that the SLC45A4 gene, encoding a plasma membrane polyamine transporter protein, is genetically associated with chronic pain in humans, providing new insights into the regulatory network between polyamine biosynthesis and neuronal excitability. Specifically, the research team conducted a genome-wide association study (GWAS) of chronic pain intensity in the UK Biobank and found a significant association between pain intensity and mutations located in the SLC45A4 gene locus.
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The research team further confirmed that in the mouse nervous system, Slc45a4 is abundantly expressed in all sensory neuron subtypes within the dorsal root ganglion, including pain receptors (nociceptors). Cellular experiments have revealed that SLC45A4 is a selective plasma membrane polyamine transporter. Cryo-electron microscopy (cryo-EM) structural analysis has revealed its regulatory domains and the basis for polyamine recognition. Mice lacking the SLC45A4 protein exhibit normal mechanical sensitivity but reduced sensitivity to persistent pain induced by noxious heat and analgesics, which is associated with reduced excitability of C-type polymodal nociceptors.
Collectively, these findings confirm that SLC45A4 is a polyamine transporter localized to the neuronal plasma membrane, and that mutations in its gene are strongly associated with the risk of chronic pain in humans. SLC45A4 may represent a potential new target for pain therapy that regulates thermal and chemical pain perception while preserving mechanical sensitivity.
Reference
Middleton S J, et al. SLC45A4 is a pain gene encoding a neuronal polyamine transporter. Nature, 2025: 1-9.