The National Center for Complementary and Integrative Health (NCCIH) Priorities for Cannabis and Cannabinoid Research.

The National Center for Complementary and Integrative Health (NCCIH), a component of the National Institutes of Health (NIH), has a broad interest in the study of the biological activities of natural products with a strong research emphasis on products for which there is compelling preclinical evidence for potential biological activity that may lead to a health benefit or treatment interventions, and/or products that are widely used by the American public. Use of cannabis for medical purposes is legal in 38 states and the District of Columbia. As a result, the use of cannabis products to treat medical conditions in the United States continues to climb without sufficient knowledge regarding risks and benefits. In keeping with NCCIH's natural product research priorities and in recognizing this gap in knowledge, NCCIH formally launched a research program in 2019 to expand research on the potential therapeutic benefit of minor cannabinoids and terpenes for the treatment of pain. This Viewpoint provides additional details and rationale for this research priority at NCCIH. In addition, NCCIH's efforts and initiatives to facilitate and coordinate an NIH research agenda focused on cannabis and cannabinoid research is described. Significance Statement Trends in the use of cannabis products to treat medical conditions continues without sufficient knowledge regarding risks and benefits. Research is needed to help the public and health care providers make informed decisions about cannabis and cannabinoids for medical purposes. NCCIH along with other NIH Institutes, Centers and Office is expanding its study on the safety, efficacy, and harms of cannabis; a complex mixture of phytochemicals that need to be studied alone and in combination.

Unmet Need: Mechanistic and Translational Studies of Sickle Cell Disease Pain as a Whole-Person Health Challenge.

Sickle cell disease (SCD) is a lifelong monogenic, autosomal-recessive blood disease that predominantly affects individuals of African descent and those who self-identify as Black or Hispanic. Common SCD pathophysiological processes include adhesion, hemolysis, hypoxia, ischemia, oxidative stress, and vaso-occlusion, which often lead to substantial comorbidities and complications. Pain is one of the most common and significant clinical complications for individuals with SCD. Despite advancements in understanding the pathophysiology of SCD, the ways in which SCD pathophysiological processes contribute to nociception and pain signaling, processing, and perception remain largely unclear. Pain management for individuals with SCD is complex and presents unique challenges that must be considered depending on the presenting pain type (eg, acute pain episode vs chronic pain). Racism, stigma (including stigma associated with opioid use), and limited resources present additional challenges. Limited research has been conducted on major clinical features of SCD pain such as its ischemic, inflammatory, and neuropathic components; on its transition from acute to chronic form and across the lifespan; and on factors influencing SCD pain perception. Research on and management of SCD pain requires a whole-person approach, bringing together investigators from multiple disciplines such as hematologists, organ biologists, pain experts, physiologists, neuroscientists, psychologists, geneticists, microbiologists, immunologists, behavioral scientists, and clinicians. Multidisciplinary cross-training, with different platforms for information dissemination and communication, could help promote basic, mechanistic, and translational research to inform the optimization of current treatment strategies and the development of novel therapies for SCD pain. PERSPECTIVE: This review presents the research challenges and negative impact of SCD pain, a grossly understudied condition in a highly underserved population. It also highlights the barriers and opportunities in SCD pain research and could help clinicians better understand current treatment strategies from the whole-person perspective.

Association of Protein and Genetic Biomarkers With Response to Lumbar Epidural Steroid Injections in Subjects With Axial Low Back Pain.

OBJECTIVE: The purpose of this observational study was to examine the association of protein and genetic biomarkers with pain and pain-related disability in individuals with axial low back pain undergoing epidural steroid injections. DESIGN: Forty-eight adults with axial low back pain undergoing an epidural steroid injection were recruited from an academic medical center. Blood samples were assayed at baseline and follow-up for plasma proteins and functional single-nucleotide polymorphisms associated with pain. Data regarding pain and function were collected at baseline and follow-up. The characteristics of responders (defined as 50% improvement in pain score) and nonresponders were compared, and the association between response and baseline biomarkers was examined. RESULTS: Thirty-five percent of subjects were responders to injection. Responders had lower baseline plasma levels of chondroitin sulfate 846 and higher neuropeptide Y and serotonin levels than nonresponders, and baseline neuropeptide Y level correlated with change in disability levels. In addition, subjects with the variant allele for the catechol-O-methyltransferase single-nucleotide polymorphism demonstrated increased odds of responding to the injection. CONCLUSIONS: These data identify candidates who may have utility for patient selection for spinal procedures and provide support for exploration in prospective studies to assess and validate their predictive ability.

AAAPT Diagnostic Criteria for Acute Pain Following Breast Surgery.

Acute pain after breast surgery decreases the quality of life of cancer survivors. Previous studies using a variety of definitions and methods report prevalence rates between 10% and 80%, which suggests the need for a comprehensive framework that can be used to guide assessment of acute pain and pain-related outcomes after breast surgery. A multidisciplinary task force with clinical and research expertise performed a focused review and synthesis and applied the 5 dimensional framework of the AAAPT (Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks [ACTTION], American Academy of Pain Medicine [AAPM], American Pain Society [APS] Pain Taxonomy) to acute pain after breast surgery. Application of the AAAPT taxonomy yielded the following: 1) Core Criteria: Location, timing, severity, and impact of breast surgery pain were defined; 2) Common Features: Character and expected trajectories were established in relevant surgical subgroups, and common pain assessment tools for acute breast surgery pain identified; 3) Modulating Factors: Biological, psychological, and social factors that modulate interindividual variability were delineated; 4) Impact/Functional Consequences: Domains of impact were outlined and defined; 5) Neurobiologic Mechanisms: Putative mechanisms were specified ranging from nerve injury, inflammation, peripheral and central sensitization, to affective and social processing of pain. PERSPECTIVE: The AAAPT provides a framework to define and guide improved assessment of acute pain after breast surgery, which will enhance generalizability of results across studies and facilitate meta-analyses and studies of interindividual variation, and underlying mechanism. It will allow researchers and clinicians to better compare between treatments, across institutions, and with other types of acute pain.

A functional substitution in the L-aromatic amino acid decarboxylase enzyme worsens somatic symptoms via a serotonergic pathway.

OBJECTIVE: Heightened somatic symptoms are reported by a wide range of patients with chronic pain and have been associated with emotional distress and physical dysfunction. Despite their clinical significance, molecular mechanisms leading to their manifestation are not understood. METHODS: We used an association study design based on a curated list of 3,295 single nucleotide polymorphisms mapped to 358 genes to test somatic symptoms reporting using the Pennebaker Inventory of Limbic Languidness questionnaire from a case-control cohort of orofacial pain (n = 1,607). A replication meta-analysis of 3 independent cohorts (n = 3,189) was followed by functional validation, including in silico molecular dynamics, in vitro enzyme assays, and measures of serotonin (5-HT) plasma concentration. RESULTS: An association with the T allele of rs11575542 coding for an arginine to glutamine substitution in the L-aromatic amino acid decarboxylase (AADC) enzyme was replicated in a meta-analysis of 3 independent cohorts. In a combined meta-analysis of all cohorts, this association reached p = 6.43 × 10-8 . In silico studies demonstrated that this substitution dramatically reduces the conformational dynamics of AADC, potentially lowering its binding capacity to a cofactor. in vitro enzymatic assays showed that this substitution reduces the maximum kinetic velocity of AADC, hence lowering 5-HT levels. Finally, plasma samples from 90 subjects showed correlation between low 5-HT levels and heightened somatic symptoms. INTERPRETATION: Using functional genomics approaches, we identified a polymorphism in the AADC enzyme that contributes to somatic symptoms through reduced levels of 5-HT. Our findings suggest a molecular mechanism underlying the pathophysiology of somatic symptoms and opens up new treatment options targeting the serotonergic system. ANN NEUROL 2019;86:168-180.

Cartilage-binding antibodies induce pain through immune complex-mediated activation of neurons.

Rheumatoid arthritis-associated joint pain is frequently observed independent of disease activity, suggesting unidentified pain mechanisms. We demonstrate that antibodies binding to cartilage, specific for collagen type II (CII) or cartilage oligomeric matrix protein (COMP), elicit mechanical hypersensitivity in mice, uncoupled from visual, histological and molecular indications of inflammation. Cartilage antibody-induced pain-like behavior does not depend on complement activation or joint inflammation, but instead on tissue antigen recognition and local immune complex (IC) formation. smFISH and IHC suggest that neuronal Fcgr1 and Fcgr2b mRNA are transported to peripheral ends of primary afferents. CII-ICs directly activate cultured WT but not FcRγ chain-deficient DRG neurons. In line with this observation, CII-IC does not induce mechanical hypersensitivity in FcRγ chain-deficient mice. Furthermore, injection of CII antibodies does not generate pain-like behavior in FcRγ chain-deficient mice or mice lacking activating FcγRs in neurons. In summary, this study defines functional coupling between autoantibodies and pain transmission that may facilitate the development of new disease-relevant pain therapeutics.

Nicotine Evoked Currents in Human Primary Sensory Neurons.

Sensory neuron nicotinic acetylcholine receptors (nAChRs) contribute to pain associated with tissue injury. However, there are marked differences between rats and mice with respect to both the properties and distribution of nAChR currents in sensory neurons. Because both species are used to understand pain signaling in humans, we sought to determine whether the currents present in either species was reflective of those present in human sensory neurons. Neurons from the L4/L5 dorsal root ganglia were obtained from adult male and female organ donors. Nicotine evoked currents were detected in 40 of 47 neurons (85%). In contrast with the naïve mouse, in which almost all nAChR currents are transient, or the rat, in which both mouse-like transient and more slowly activating and inactivating currents are detected, all the currents in human DRG neurons were slow, but slower than those in the rat. Currents were blocked by the nAChR antagonists mecamylamine (30 µmol/L), but not by the TRPA1 selective antagonist HC-030031 (10 µmol/L). Single cell polymerase chain reaction analysis of nicotinic receptor subunit expression in human DRG neurons are consistent with functional data indicating that receptor expression is detected 85 ± 2.1% of neurons assessed (n = 48, from 4 donors). The most prevalent coexpression pattern was α3/ß2 (95 ± 4% of neurons with subunits), but α7 subunits were detected in 70 ± 3.4% of neurons. These results suggest that there are not only species differences in the sensory neuron distribution of nAChR currents between rodent and human, but that the subunit composition of the channel underlying human nAChR currents may be different from those in the mouse or rat. PERSPECTIVE: The properties and distribution of nicotine evoked currents in human sensory neurons were markedly different from those previously observed in mice and rats. These observations add additional support to the suggestion that human sensory neurons may be an essential screening tool for those considering moving novel therapeutics targeting primary afferents into clinical trials.

Genome-wide association reveals contribution of MRAS to painful temporomandibular disorder in males.

Painful temporomandibular disorders (TMDs) are the leading cause of chronic orofacial pain, but its underlying molecular mechanisms remain obscure. Although many environmental factors have been associated with higher risk of developing painful TMD, family and twin studies support a heritable genetic component as well. We performed a genome-wide association study assuming an additive genetic model of TMD in a discovery cohort of 999 cases and 2031 TMD-free controls from the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study. Using logistic models adjusted for sex, age, enrollment site, and race, we identified 3 distinct loci that were significant in combined or sex-segregated analyses. A single-nucleotide polymorphism on chromosome 3 (rs13078961) was significantly associated with TMD in males only (odds ratio = 2.9, 95% confidence interval: 2.02-4.27, P = 2.2 × 10). This association was nominally replicated in a meta-analysis of 7 independent orofacial pain cohorts including 160,194 participants (odds ratio = 1.16, 95% confidence interval: 1.0-1.35, P = 2.3 × 10). Functional analysis in human dorsal root ganglia and blood indicated this variant is an expression quantitative trait locus, with the minor allele associated with decreased expression of the nearby muscle RAS oncogene homolog (MRAS) gene (beta = -0.51, P = 2.43 × 10). Male mice, but not female mice, with a null mutation of Mras displayed persistent mechanical allodynia in a model of inflammatory pain. Genetic and behavioral evidence support a novel mechanism by which genetically determined MRAS expression moderates the resiliency to chronic pain. This effect is male-specific and may contribute to the lower rates of painful TMD in men.

CACNG2 polymorphisms associate with chronic pain after mastectomy.

Chronic postmastectomy pain (PMP) imposes a major burden on the quality of life of the ever-increasing number of long-term survivors of breast cancer. An earlier report by Nissenbaum et al. claimed that particular polymorphisms in the gene CACNG2 are associated with the risk of developing chronic PMP after breast surgery (Nissenbaum J, Devor M, Seltzer Z, Gebauer M, Michaelis M, Tal M, Dorfman R, Abitbul-Yarkoni M, Lu Y, Elahipanah T, delCanho S, Minert A, Fried K, Persson AK, Shpigler H, Shabo E, Yakir B, Pisante A, Darvasi A. Susceptibility to chronic pain following nerve injury is genetically affected by CACNG2. Genome Res 2010;20:1180-90). This information is important because in principle, it can inform the surgical, radiological, and chemotherapeutic decision-making process in ways that could mitigate the increased risk of chronic pain. In this study, we revisited this claim by independently evaluating the proposed marker haplotype using 2 different patient cohorts recruited in different research settings. Meta-analysis of these new postmastectomy cohorts and the original cohort confirmed significant association of the CACNG2 haplotype with PMP. In addition, we tested whether the same markers would predict chronic postsurgical pain in men who underwent surgery for inguinal hernia repair, and whether there is significant genetic association with cutaneous thermal sensitivity in postmastectomy and postherniotomy patients. We found that the biomarker is selective because it did not predict pain after laparoscopic hernia repair and was not associated with pain sensitivity to experimentally applied noxious thermal stimuli. We conclude that the A-C-C haplotype at the 3 single-nucleotide polymorphisms (rs4820242, rs2284015, and rs2284017) in the CACNG2 gene is associated with increased risk of developing PMP. This information may advance current knowledge on pathophysiology of PMP and serve as a step forward in the prediction of clinical outcomes and personalized pain management.

Second edition of SIMPAR's "Feed Your Destiny" workshop: the role of lifestyle in improving pain management.

This review is aimed to summarize the latest data regarding pain and nutrition, which have emerged during the second edition of Feed Your Destiny (FYD). Theme presentations and interactive discussions were held at a workshop on March 30, 2017, in Florence, Italy, during the 9th Annual Meeting of Study in Multidisciplinary Pain Research, where an international faculty, including recognized experts in nutrition and pain, reported the scientific evidence on this topic from various perspectives. Presentations were divided into two sections. In the initial sessions, we analyzed the outcome variables and methods of measurement for health claims pertaining to pain proposed under Regulation EC No 1924/2006 of the European Parliament and of the Council of 20 December 2006 on nutrition and health claims made on foods. Moreover, we evaluated how the Mediterranean diet can have a potential impact on pain, gastrointestinal disorders, obesity, cancer, and aging. Second, we discussed the evidence regarding vitamin D as a nutraceutical that may contribute to pain control, evaluating the interindividual variability of pain nature and nurture, and the role of micro-RNAs (miRNAs), polyunsaturated omega 3 fatty acids, and phenolic compounds, with a final revision of the clinical role of nutrition in tailoring pain therapy. The key take-home message provided by the FYD workshop was that a balanced, personalized nutritional regimen might play a role as a synergic strategy that can improve management of chronic pain through a precision medicine approach.

Pain catastrophizing is associated with poorer health-related quality of life in pediatric patients with sickle cell disease.

BACKGROUND: Sickle cell disease (SCD) is an inherited disorder of the red blood cells and is associated with chronic multisystem involvement. While SCD has been associated with poorer health-related quality of life (HRQoL), there is a paucity of data on the relationship of psychological covariates other than anxiety and depression and quality of life (QoL) in children with SCD. MATERIALS AND METHODS: We performed a cross-sectional study of psychological factors, HRQoL, and pain-related outcomes in participants with SCD and race-matched controls as part of a larger study of experimental pain phenotyping. RESULTS: Pain catastrophizing was inversely correlated with HRQoL measured by the PedsQL™ Generic Core Scale in children with SCD, while this was not noted in control participants. Psychological factors, such as anxiety and depressive symptoms, were also associated with poorer HRQoL in both children with SCD and controls. We did not find an association of psychological factors with prior health care utilization. Psychological factors such as anxiety and depressive symptoms were inversely correlated with pain interference, but not pain intensity in SCD. CONCLUSION: Catastrophizing is associated with poorer HRQoL in SCD, but in this study, it was not associated with pain intensity or interference and health care utilization in children with SCD. Further studies are needed to fully define the association of psychological factors including catastrophizing with QoL, pain burden, and SCD outcomes.

Association of genetic variation in COMT gene with pain related to sickle cell disease in patients from the walk-PHaSST study.

BACKGROUND: Vaso-occlusive pain episodes (VOEs) are the hallmark of sickle cell disease (SCD), and our current understanding of disease biology, treatment, and psychological covariates does not adequately explain the variability of pain in SCD. Functional variants in catechol-O-methyltransferase (COMT) gene contribute to variability in pain perception, but their impact on pain perception in African American SCD patients is not well known. METHODS: We studied COMT single-nucleotide polymorphisms (SNPs) rs6269, rs4633, rs4818, rs4680, and rs165599 to determine their relationship to patient self-reported pain, the number of acute VOEs, and their impact on daily life and health care utilization in 438 hemoglobin SS patients who participated in the walk-PHaSST study. RESULTS: In women, two risk SNPs (rs4633 and rs165599) and the corresponding haplotype (ATCAA) were associated with increased frequency of pain-related emergency room visit. CONCLUSION: COMT functional variants may predispose SCD patients to worse acute pain in women. The association of COMT variants with the intensity of self-reported acute pain warrants further genetic study of pain perception in SCD.

Quantitative sensory testing is feasible and is well-tolerated in patients with sickle cell disease following a vaso-occlusive episode.

INTRODUCTION: Sickle cell disease (SCD) is an inherited blood disorder characterized by abnormally shaped sickle cells. The hallmark of this disease is intermittent, painful vaso-occlusive episodes (VOE), but a subset of individuals with SCD experience chronic pain. The mechanism of transition to chronic pain is not well understood in SCD, but there is evidence of altered pain processing in individuals with SCD. The impact of VOE on pain sensitivity is not established. The objective of this study was to determine the feasibility and tolerability of quantitative sensory testing (QST) in SCD following a VOE to better understand the contribution of VOE to the development of chronic pain. METHODS: As part of a larger pain sensitivity study, pediatric patients with SCD were offered QST following a VOE-related Emergency Room visit or inpatient hospitalization. The feasibility of recruitment and completion of QST was measured, and tolerability of QST was determined using post-QST assessments of pain, and compared with measurements at steady state. RESULTS: Ten participants completed QST following a VOE. The median age was 16.5, and 60% were female. Overall, 10 of 16 (62.5%) patients approached for QST following VOE completed QST. This included 8 of 12 patients who had previously completed QST at steady state. There were no statistically significant differences in pain intensity and Gracely Box scores after QST following a VOE, when compared to steady-state QST. CONCLUSION: QST is feasible and is well-tolerated following a VOE in patients with SCD. Large prospective studies are needed to determine the impact of VOE on experimental pain sensitivity and must take into account all factors contributing to pain sensitivity.

Central sensitization associated with low fetal hemoglobin levels in adults with sickle cell anemia.

BACKGROUND AND AIMS: Pain is the hallmark of sickle cell anemia (SCA), presenting as recurrent acute events or chronic pain. Central sensitization, or enhanced excitability of the central nervous system, alters pain processing and contributes to the maintenance of chronic pain. Individuals with SCA demonstrate enhanced sensitivity to painful stimuli however central mechanisms of pain have not been fully explored. We hypothesized that adults with SCA would show evidence of central sensitization as observed in other diseases of chronic pain. METHODS: We conducted a prospective study of static and dynamic quantitative sensory tests in 30 adults with SCA and 30 matched controls. RESULTS: Static thermal testing using cold stimuli showed lower pain thresholds (p=0.04) and tolerance (p=0.04) in sickle cell subjects, but not for heat. However, SCA subjects reported higher pain ratings with random heat pulses (p<0.0001) and change in scores with temporal summation at the heat pain threshold (p=0.002). Similarly, with the use of pressure pain stimuli, sickle cell subjects reported higher pain ratings (p=0.04), but not higher pressure pain tolerance/thresholds or allodynia to light tactile stimuli. Temporal summation pain score changes using 2 pinprick probes (256 and 512mN) were significantly greater (p=0.004 and p=0.008) with sickle cell, and delayed recovery was associated with lower fetal hemoglobin (p=0.002 and 0.003). CONCLUSIONS: Exaggerated temporal summation responses provide evidence of central sensitization in SCA. IMPLICATIONS: The association with fetal hemoglobin suggests this known SCA modifier may have a therapeutic role in modulating central sensitization.

Pain in women.

Men and women are different in response to experimental painful stimulation, in pain attitude such as reporting pain and pain coping behavior, in symptoms and signs of painful disorders and in response to pain treatment. Both acute and chronic pain conditions have diverse prevalence among the sexes. Overall, women have more than twice higher prevalence in painful disorders compared to men. Here I review putative mechanisms underlying sex differences in pain, including genetic factors that have sex-specific or sex-biased effects controlling pain and analgesia.

Psychological Characteristics and Pain Frequency Are Associated With Experimental Pain Sensitivity in Pediatric Patients With Sickle Cell Disease.

Sickle cell disease (SCD) is associated with episodes of severe vaso-occlusive pain beginning in infancy with a subset of patients with SCD transitioning to chronic pain. Response to experimental pain using quantitative sensory testing in these patients suggests altered pain processing. The objectives of this study were to characterize sensitivity to multiple modalities of experimental pain stimuli and to interrogate the relationship of psychological covariates, clinical pain burden, and pain-related outcomes to experimental pain sensitivity in children with SCD compared with healthy individuals of similar age and sex. Cross-sectional assessments of psychological characteristics were performed, and quantitative sensory testing methods were used to measure experimental pain sensitivity in children age 8 to 21 years. Anxiety, depressive symptoms, catastrophizing, and somatization were found to be associated with increased sensitivity to experimental pain stimuli. Increased frequency of painful episodes in SCD was associated with decreased sensitivity to heat pain and decreased mechanical temporal summation. These data suggest that careful consideration be given to psychological factors, age, sex, and clinical burden of pain when studying response to experimental pain in SCD. PERSPECTIVE: In this study of patients with SCD, a condition associated with recurrent acute or chronic pain, psychological factors such as depression, anxiety, and catastrophizing are associated with increased sensitivity to experimental pain stimuli. Further study is need to delineate the role of these factors in chronic SCD pain.

miR-183 cluster scales mechanical pain sensitivity by regulating basal and neuropathic pain genes.

Nociception is protective and prevents tissue damage but can also facilitate chronic pain. Whether a general principle governs these two types of pain is unknown. Here, we show that both basal mechanical and neuropathic pain are controlled by the microRNA-183 (miR-183) cluster in mice. This single cluster controls more than 80% of neuropathic pain-regulated genes and scales basal mechanical sensitivity and mechanical allodynia by regulating auxiliary voltage-gated calcium channel subunits α2δ-1 and α2δ-2. Basal sensitivity is controlled in nociceptors, and allodynia involves TrkB+ light-touch mechanoreceptors. These light-touch-sensitive neurons, which normally do not elicit pain, produce pain during neuropathy that is reversed by gabapentin. Thus, a single microRNA cluster continuously scales acute noxious mechanical sensitivity in nociceptive neurons and suppresses neuropathic pain transduction in a specific, light-touch-sensitive neuronal type recruited during mechanical allodynia.

Effect of Human Genetic Variability on Gene Expression in Dorsal Root Ganglia and Association with Pain Phenotypes.

Dorsal root ganglia (DRG) relay sensory information to the brain, giving rise to the perception of pain, disorders of which are prevalent and burdensome. Here, we mapped expression quantitative trait loci (eQTLs) in a collection of human DRGs. DRG eQTLs were enriched within untranslated regions of coding genes of low abundance, with some overlapping with other brain regions and blood cell cis-eQTLs. We confirm functionality of identified eQTLs through their significant enrichment within open chromatin and highly deleterious SNPs, particularly at the exon level, suggesting substantial contribution of eQTLs to alternative splicing regulation. We illustrate pain-related genetic association results explained by DRG eQTLs, with the strongest evidence for contribution of the human leukocyte antigen (HLA) locus, confirmed using a mouse inflammatory pain model. Finally, we show that DRG eQTLs are found among hits in numerous genome-wide association studies, suggesting that this dataset will help address pain components of non-pain disorders.

Voltage-gated Na+ currents in human dorsal root ganglion neurons.

Available evidence indicates voltage-gated Na+ channels (VGSCs) in peripheral sensory neurons are essential for the pain and hypersensitivity associated with tissue injury. However, our understanding of the biophysical and pharmacological properties of the channels in sensory neurons is largely based on the study of heterologous systems or rodent tissue, despite evidence that both expression systems and species differences influence these properties. Therefore, we sought to determine the extent to which the biophysical and pharmacological properties of VGSCs were comparable in rat and human sensory neurons. Whole cell patch clamp techniques were used to study Na+ currents in acutely dissociated neurons from human and rat. Our results indicate that while the two major current types, generally referred to as tetrodotoxin (TTX)-sensitive and TTX-resistant were qualitatively similar in neurons from rats and humans, there were several differences that have important implications for drug development as well as our understanding of pain mechanisms.