Nicholas Gregory

All Publications

• Peripheral Nerve Stimulation for Pudendal Neuralgia: A Technical Note. Pain medicine (Malden, Mass.) Gregory, N. S., Terkawi, A. S., Prabhakar, N. K., Tran, J. V., Salmasi, V., Hah, J. M. 2020; 21 (Supplement_1): S51–S55

  Abstract

  BACKGROUND: Pudendal neuropathy is a chronic, disabling form of perineal pain that involves the pudendal nerve, a mixed somatic and autonomic nerve that originates from sacral nerve roots. Peripheral nerve stimulation of the pudendal nerve can be useful to decrease symptom burden in patients who have failed initial conservative treatment modalities.METHODS: In this manuscript, we describe an approach to the placement of a peripheral nerve stimulator for the treatment of pudendal neuralgia. We present a case of complex pelvic neuropathy and review the factors that lead to successful placement. Technical aspects of stimulator placement and ultrasound landmarks are reviewed.RESULTS: A lateral to medial approach with ultrasound guidance at the level of the ischial spine is likely to facilitate proper lead placement along the course of the pudendal nerve. Aftercare and adherence to postimplant activity restrictions-particularly avoiding use of the extremes of hip flexion and extension for four weeks-lead to the absence of lead migration.CONCLUSIONS: Pudendal nerve stimulation is an emerging technique for neuromodulation of refractory pudendal neuralgia. Ultrasound-guided pudendal nerve stimulation is a viable technique for neuromodulation of pudendal neuralgia. Optimization of patient selection, ultrasound guidance, and proper adherence to postimplant activity restrictions may be helpful for long-term therapeutic success.

  View details for DOI 10.1093/pm/pnaa171

  View details for PubMedID 32804222

• P2X4 Receptors on Muscle Macrophages Are Required for Development of Hyperalgesia in an Animal Model of Activity-Induced Muscle Pain MOLECULAR NEUROBIOLOGY Oliveira-Fusaro, M., Gregory, N. S., Kolker, S. J., Rasmussen, L., Allen, L. H., Sluka, K. A. 2020; 57 (4): 1917-1929

  Abstract

  Activity-induced pain is common in those with chronic musculoskeletal pain and limits participation in daily activities and exercise. Our laboratory developed a model of activity-induced pain and shows that depletion of muscle macrophages prevents development of hyperalgesia. Adenosine triphosphate (ATP) is released from fatiguing muscle and activates purinergic receptors (P2X), and P2X4 receptors are expressed on macrophages. We hypothesized that exercise releases ATP to activate P2X4 receptors on muscle macrophages, which subsequently release interleukin-1β (IL-1β) to produce hyperalgesia. In an animal model of activity-induced pain, using male and female C57BL6/J mice, we show increased expression of P2X4 on muscle macrophages, and blockade of P2X4 receptors in muscle prevented development of hyperalgesia. Using a lentivirus expressing an artificial micro-RNA to P2X4 under the control of a CD68 promoter, we decreased expression of P2X4 mRNA in cultured macrophages, decreased expression of P2X4 protein in muscle macrophages in vivo, and prevented development of activity-induced hyperalgesia. We further show that macrophages primed with LPS differentially released IL-1β when treated with ATP in neutral or acidic pH. Lastly, blockade of IL-1β in muscle prevented development of hyperalgesia in this model. Thus, our data suggest that P2X4 receptors could be a valid pharmacological target to control activity-induced muscle pain experienced by patients with chronic musculoskeletal pain.

  View details for DOI 10.1007/s12035-019-01852-x

  View details for Web of Science ID 000505368600001

  View details for PubMedID 31898158

  View details for PubMedCentralID PMC7124976

• Acid Sensing Ion Channel 1a (ASIC1a) Mediates Activity-induced Pain by Modulation of Heteromeric ASIC Channel Kinetics NEUROSCIENCE Gregory, N. S., Gautam, M., Benson, C. J., Sluka, K. A. 2018; 386: 166-174

  Abstract

  Chronic muscle pain is acutely worsened by exercise. Acid sensing ion channels (ASIC) are heteromeric channels expressed in muscle sensory neurons that detect decreases in pH. We have previously shown ASIC3 is important in activity-induced hyperalgesia. However, ASICs form heteromers with ASIC1a being a key component in sensory neurons. Therefore, we studied the role of ASIC1a in mice using behavioral pharmacology and genetic deletion in a model of activity-induced hyperalgesia. We found ASIC1a-/- mice developed mechanical hyperalgesia similar to wild-type mice, but antagonism of ASIC1a, with psalmotoxin, prevented development of mechanical hyperalgesia in wild-type mice, but not in ASIC1a-/- mice. To explain this discrepancy, we then performed electrophysiology studies of ASICs and examined the effects of psalmotoxin on ASIC heteromers. We expressed ASIC1a, 2 and 3 heteromers or ASIC1 and 3 heteromers in CHO cells, and examined the effects of psalmotoxin on pH sensitivity. Psalmotoxin significantly altered the properties of ASIC hetomeric channels. Specifically, in ASIC1a/2/3 heteromers, psalmotoxin slowed the kinetics of desensitization, slowed the recovery from desensitization, and inhibited pH-dependent steady-state desensitization, but had no effect on pH-evoked current amplitudes. We found a different pattern in ASIC1a/3 heteromers. There was a significant leftward shift in the pH dose response of steady-state desensitization and decrease in pH-evoked current amplitudes. These results suggest that blockade of ASIC1a modulates the kinetics of heteromeric ASICs to prevent development of activity-induced hyperalgesia. These data suggest ASIC1a is a key subunit in heteromeric ASICs and may be a pharmacological target for treatment of musculoskeletal pain.

  View details for DOI 10.1016/j.neuroscience.2018.06.033

  View details for Web of Science ID 000440325500013

  View details for PubMedID 29964154

• ASIC3 Is Required for Development of Fatigue-Induced Hyperalgesia MOLECULAR NEUROBIOLOGY Gregory, N. S., Brito, R. G., Oliveira Fusaro, M. G., Sluka, K. A. 2016; 53 (2): 1020-1030

  Abstract

  An acute bout of exercise can exacerbate pain, hindering participation in regular exercise and daily activities. The mechanisms underlying pain in response to acute exercise are poorly understood. We hypothesized that proton accumulation during muscle fatigue activates acid-sensing ion channel 3 (ASIC3) on muscle nociceptors to produce hyperalgesia. We investigated the role of ASIC3 using genetic and pharmacological approaches in a model of fatigue-enhanced hyperalgesia. This model uses two injections of pH 5.0 saline into muscle in combination with an electrically induced fatigue of the same muscle just prior to the second injection of acid to induce mechanical hyperalgesia. We show a significant decrease in muscle force and decrease in muscle pH after 6 min of electrical stimulation. Genetic deletion of ASIC3 using knockout mice and pharmacological blockade of ASIC3 with APETx2 in muscle prevents the fatigue-enhanced hyperalgesia. However, ASIC3(-/-) mice and APETx2 have no effect on the fatigue response. Genetic deletion of ASIC3 in primary afferents innervating muscle using an HSV-1 expressing microRNA (miRNA) to ASIC3 surprisingly had no effect on the development of the hyperalgesia. Muscle fatigue increased the number of macrophages in muscle, and removal of macrophages from muscle with clodronate liposomes prevented the development of fatigue-enhanced hyperalgesia. Thus, these data suggest that fatigue reduces pH in muscle that subsequently activates ASIC3 on macrophages to enhance hyperalgesia to muscle insult.

  View details for DOI 10.1007/s12035-014-9055-4

  View details for Web of Science ID 000370187100018

  View details for PubMedID 25577172

  View details for PubMedCentralID PMC4499332

• Regular physical activity prevents chronic pain by altering resident muscle macrophage phenotype and increasing interleukin-10 in mice PAIN Leung, A., Gregory, N. S., Allen, L. H., Sluka, K. A. 2016; 157 (1): 70-79

  Abstract

  Regular physical activity in healthy individuals prevents development of chronic musculoskeletal pain; however, the mechanisms underlying this exercise-induced analgesia are not well understood. Interleukin-10 (IL-10), an antiinflammatory cytokine that can reduce nociceptor sensitization, increases during regular physical activity. Since macrophages play a major role in cytokine production and are present in muscle tissue, we propose that physical activity alters macrophage phenotype to increase IL-10 and prevent chronic pain. Physical activity was induced by allowing C57BL/6J mice free access to running wheels for 8 weeks and compared to sedentary mice with no running wheels. Using immunohistochemical staining of the gastrocnemius muscle to label regulatory (M2, secretes antiinflammatory cytokines) and classical (M1, secretes proinflammatory cytokines) macrophages, the percentage of M2-macrophages increased significantly in physically active mice (68.5% ± 4.6% of total) compared with sedentary mice (45.8% ± 7.1% of total). Repeated acid injections into the muscle enhanced mechanical sensitivity of the muscle and paw in sedentary animals, which does not occur in physically active mice; no sex differences occur in either sedentary or physically active mice. Blockade of IL-10 systemically or locally prevented the analgesia in physically active mice, ie, mice developed hyperalgesia. Conversely, sedentary mice pretreated systemically or locally with IL-10 had reduced hyperalgesia after repeated acid injections. Thus, these results suggest that regular physical activity increases the percentage of regulatory macrophages in muscle and that IL-10 is an essential mediator in the analgesia produced by regular physical activity.

  View details for DOI 10.1097/j.pain.0000000000000312

  View details for Web of Science ID 000377104800008

  View details for PubMedID 26230740

  View details for PubMedCentralID PMC4685958

• Effect of Intramuscular Protons, Lactate, and ATP on Muscle Hyperalgesia in Rats PLOS ONE Gregory, N. S., Whitley, P. E., Sluka, K. A. 2015; 10 (9): e0138576

  Abstract

  Chronic muscle pain is a significant health problem leading to disability[1]. Muscle fatigue can exacerbate muscle pain. Metabolites, including ATP, lactate, and protons, are released during fatiguing exercise and produce pain in humans. These substances directly activate purinergic (P2X) and acid sensing ion channels (ASICs) on muscle nociceptors, and when combined, produce a greater increase in neuron firing than when given alone. Whether the enhanced effect of combining protons, lactate, and ATP is the sum of individual effects (additive) or more than the sum of individual effects (synergistic) is unknown. Using a rat model of muscle nociceptive behavior, we tested each of these compounds individually over a range of physiologic and supra-physiologic concentrations. Further, we combined all three compounds in a series of dilutions and tested their effect on muscle nociceptive behavior. We also tested a non-hydrolyzable form of ATP (α,β-meATP) alone and in combination with lactate and acidic pH. Surprisingly, we found no dose-dependent effect on muscle nociceptive behavior for protons, lactate, or ATP when given alone. We similarly found no effect after application of each two-metabolite combination. Only pH 4 saline and α,β-meATP produced hyperalgesia when given alone. When all 3 substances were combined, however, ATP (2.4μm), lactate (10mM), and acidic pH (pH 6.0) produced an enhanced effect greater than the sum of the effects of the individual components, i.e. synergism. α,β me ATP (3nmol), on the other hand, showed no enhanced effects when combined with lactate (10mM) or acidic pH (pH 6.0), i.e. additive. These data suggest that combining fatigue metabolites in muscle produces a synergistic effect on muscle nociception.

  View details for DOI 10.1371/journal.pone.0138576

  View details for Web of Science ID 000361769400112

  View details for PubMedID 26378796

  View details for PubMedCentralID PMC4574767

• The dichotomized role for acid sensing ion channels in musculoskeletal pain and inflammation NEUROPHARMACOLOGY Sluka, K. A., Gregory, N. S. 2015; 94: 58-63

  Abstract

  Chronic muscle pain affects between 11 and 24% of the world's population with the majority of people experiencing musculoskeletal pain at some time in their life. Acid sensing ion channels (ASICs) are important sensors of modest decreases in extracellular pH that occur within the physiological range. These decreases in extracellular pH occur in response to inflammation, fatiguing exercise, and ischemia. Further, injection of acidic saline into muscle produces enhanced nociceptive behaviors in animals and pain in human subjects. Of the different types of ASICs, ASIC3 and ASIC1 have been implicated in transmission of nociceptive information from the musculoskeletal system. The current review will provide an overview of the evidence for ASIC3 and ASIC1 in musculoskeletal pain in both inflammatory and non-inflammatory models. This article is part of the Special Issue entitled 'Acid-Sensing Ion Channels in the Nervous System'.

  View details for DOI 10.1016/j.neuropharm.2014.12.013

  View details for Web of Science ID 000356735000009

  View details for PubMedID 25582293

  View details for PubMedCentralID PMC4458430

• Anatomical and physiological factors contributing to chronic muscle pain. Current topics in behavioral neurosciences Gregory, N. S., Sluka, K. A. 2014; 20: 327-48

  Abstract

  Chronic muscle pain remains a significant source of suffering and disability despite the adoption of pharmacologic and physical therapies. Muscle pain is mediated by free nerve endings distributed through the muscle along arteries. These nerves project to the superficial dorsal horn and are transmitted primarily through the spinothalamic tract to several cortical and subcortical structures, some of which are more active during the processing of muscle pain than other painful conditions. Mechanical forces, ischemia, and inflammation are the primary stimuli for muscle pain, which is reflected in the array of peripheral receptors contributing to muscle pain-ASIC, P2X, and TRP channels. Sensitization of peripheral receptors and of central pain processing structures are both critical for the development and maintenance of chronic muscle pain. Further, variations in peripheral receptors and central structures contribute to the significantly greater prevalence of chronic muscle pain in females.

  View details for DOI 10.1007/7854_2014_294

  View details for PubMedID 24633937

• Fatigue-enhanced hyperalgesia in response to muscle insult: Induction and development occur in a sex-dependent manner PAIN Gregory, N. S., Gibson-Corley, K., Frey-Law, L., Sluka, K. A. 2013; 154 (12): 2668-2676

  Abstract

  Chronic muscle pain affects 20-50% of the population, is more common in women than men, and is associated with increased pain during physical activity and exercise. Muscle fatigue is common in people with chronic muscle pain, occurs in response to exercise, and is associated with release of fatigue metabolites. Fatigue metabolites can sensitize muscle nociceptors, which could enhance pain with exercise. Using a mouse model we tested whether fatigue of a single muscle, induced by electrical stimulation, resulted in enhanced muscle hyperalgesia and if the enhanced hyperalgesia was more pronounced in female mice. Muscle fatigue was induced in combination with a sub-threshold muscle insult (2 injections of pH 5.0 saline) in male and female mice. We show that male and female mice, fatigued immediately prior to muscle insult in the same muscle, develop similar muscle hyperalgesia 24 hours later. However, female mice also develop hyperalgesia when muscle fatigue and muscle insult occur in different muscles, and when muscle insult is administered 24 hours after fatigue in the same muscle. Further, hyperalgesia lasts significantly longer in females. Finally, muscle insult with or without muscle fatigue results in minimal inflammatory changes in the muscle itself, and sex differences are not related to estradiol (ovariectomy) or changes in brainstem activity (pNR1). Thus, the current model mimics muscle fatigue-induced enhancement of pain observed in chronic muscle pain conditions in the human population. Interactions between fatigue and muscle insult may underlie the development of chronic widespread pain with an associated female predominance observed in human subjects.

  View details for DOI 10.1016/j.pain.2013.07.047

  View details for Web of Science ID 000327596200015

  View details for PubMedID 23906552

  View details for PubMedCentralID PMC3957416

• An Overview of Animal Models of Pain: Disease Models and Outcome Measures JOURNAL OF PAIN Gregory, N. S., Harris, A. L., Robinson, C. R., Dougherty, P. M., Fuchs, P. N., Sluka, K. A. 2013; 14 (11): 1255-1269

  Abstract

  Pain is ultimately a perceptual phenomenon. It is built from information gathered by specialized pain receptors in tissue, modified by spinal and supraspinal mechanisms, and integrated into a discrete sensory experience with an emotional valence in the brain. Because of this, studying intact animals allows the multidimensional nature of pain to be examined. A number of animal models have been developed, reflecting observations that pain phenotypes are mediated by distinct mechanisms. Animal models of pain are designed to mimic distinct clinical diseases to better evaluate underlying mechanisms and potential treatments. Outcome measures are designed to measure multiple parts of the pain experience, including reflexive hyperalgesia measures, sensory and affective dimensions of pain, and impact of pain on function and quality of life. In this review, we discuss the common methods used for inducing each of the pain phenotypes related to clinical pain syndromes as well as the main behavioral tests for assessing pain in each model.Understanding animal models and outcome measures in animals will assist in translating data from basic science to the clinic.

  View details for DOI 10.1016/j.jpain.2013.06.008

  View details for Web of Science ID 000327047900001

  View details for PubMedID 24035349

  View details for PubMedCentralID PMC3818391