Studying human nociceptors: from fundamentals to clinic

Abstract

Chronic pain affects one in five of the general population and is the third most important cause of disability-adjusted life-years globally. Unfortunately, treatment remains inadequate due to poor efficacy and tolerability. There has been a failure in translating promising preclinical drug targets into clinic use. This reflects challenges across the whole drug development pathway, from preclinical models to trial design. Nociceptors remain an attractive therapeutic target: their sensitization makes an important contribution to many chronic pain states, they are located outside the blood–brain barrier, and they are relatively specific. The past decade has seen significant advances in the techniques available to study human nociceptors, including: the use of corneal confocal microscopy and biopsy samples to observe nociceptor morphology, the culture of human nociceptors (either from surgical or post-mortem tissue or using human induced pluripotent stem cell derived nociceptors), the application of high throughput technologies such as transcriptomics, the in vitro and in vivo electrophysiological characterization through microneurography, and the correlation with pain percepts provided by quantitative sensory testing. Genome editing in human induced pluripotent stem cell-derived nociceptors enables the interrogation of the causal role of genes in the regulation of nociceptor function. Both human and rodent nociceptors are more heterogeneous at a molecular level than previously appreciated, and while we find that there are broad similarities between human and rodent nociceptors there are also important differences involving ion channel function, expression, and cellular excitability. These technological advances have emphasized the maladaptive plastic changes occurring in human nociceptors following injury that contribute to chronic pain. Studying human nociceptors has revealed new therapeutic targets for the suppression of chronic pain and enhanced repair. Cellular models of human nociceptors have enabled the screening of small molecule and gene therapy approaches on nociceptor function, and in some cases have enabled correlation with clinical outcomes. Undoubtedly, challenges remain. Many of these techniques are difficult to implement at scale, current induced pluripotent stem cell differentiation protocols do not generate the full diversity of nociceptor populations, and we still have a relatively poor understanding of inter-individual variation in nociceptors due to factors such as age, sex, or ethnicity. We hope our ability to directly investigate human nociceptors will not only aid our understanding of the fundamental neurobiology underlying acute and chronic pain but also help bridge the translational gap.

Peripheral Voltage-Gated Cation Channels in Neuropathic Pain and Their Potential as Therapeutic Targets

“…Several recent reviews have commented on the slow translation between animal studies and the development of new therapeutic agents for use in the clinic ( 48 , 475 , 479 ). This reflects the self-evident differences between the human and rodent nervous systems ( 480 ).…”

“…This reflects the self-evident differences between the human and rodent nervous systems ( 480 ). It is already known that both rodent and human and nociceptors are more heterogeneous at a molecular level than previously appreciated, and although there are broad similarities between human and rodent nociceptors there are also important differences involving ion channel function, expression, and cellular excitability ( 356 , 479 ). For example, murine SCN11A which codes for Na v 1.9 is only 75% identical to the human gene ( 114 ).…”

“…Up until recently there were few feasible methodologies available for study of human nerves. However, recent advances in technology and methodology have increased the feasibility of human studies ( 356 , 479 ). For example, nociceptor morphology can be observed using biopsy samples ( 481 ) and cultured human nociceptors ( 482 ).…”

“…Microneurography which allows i n vivo recording of nociceptor axonal electrical activity in humans has been available for many years ( 489 ). Technological improvements have shown that the specific C-fiber subpopulation affected (mechanoinsensitive vs. non-mechanoceptive) depends on the source of neuropathic pain and the type of neuropathy ( 479 , 490 ) Modern microneurography approaches will thus play a role in the application of personalized medicine approaches to individual patients.…”

In silico Identification of Key Factors Driving the Response of Muscle Sensory Neurons to Noxious Stimuli

“…While a few studies have investigated the similarities and differences between the molecular profiles of human and mouse nociceptors (Mogil, 2019), understanding how nociceptive mechanisms translate from one species to another requires direct comparisons between them. Although advancement in technologies like transcriptomics and microneurography have allowed for a deeper in vitro and in vivo investigation of human nociceptors, such opportunities are limited due to the scale and diversity of human nociceptor populations (Middleton et al, 2021). Until we can reliably assess human nociceptors, animal models remain a necessary tool to gain a causal and mechanistic understanding of the role of different proteins involved in nociception.…”