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Paul Green, PhD

TitleProfessor
InstitutionUniversity of California San Francisco
DepartmentPreventive & Restor Dent Sci
Address513 Parnassus Ave, Med Sci
San Francisco CA 94122
Phone415-476-4902
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    My recent research has focused on mechanisms underlying chronic muscle pain, a very common clinical complaint that is extremely difficult to treat, in large part due to the lack of understanding of underlying mechanisms. I have developed two new animals models of ergonomic muscle pain (vibration and eccentric exercise), which together with inflammatory mediator-induced muscle pain will facilitate our investigation into the cellular mechanisms underlying the critical transition from acute to chronic muscle pain. In collaboration with Drs. Dina, Alvarez and Levine, we have found that the inflammatory cytokine, interleukin-6, that is produced during acute muscle inflammation mediates the production of a chronic-latent hyperalgesic state in which a subsequent exposure to inflammatory mediators produce a markedly prolonged mechanical hyperalgesia (i.e. analogous to transition from acute to chronic muscle pain) (Dina et al., Neuroscience 152:521-25, 2008; Alvarez et al, Eur J Neurosci 32:819-25, 2010). Furthermore, we have discovered that chronic-latent hyperalgesia produced by the inflammogen, carrageenan, is dependent on protein kinase Ce, a second messenger implicated in long-lasting plasticity in cutaneous nociceptors (Dina et al., J Pain 9:457-62, 2008). We have also observed that exposure to vibration produces neuropathic-like changes in the nociceptor (Chen et al., Pain 151:460-6, 2010). Vibration or eccentric exercise induced muscle pain appears to be restricted to one nociceptor phenotype, the isolectin B4-positive nociceptor (Alvarez, et al., Exp Neurol 233:859-65, 2012).
    I have also helped develop animal models of fibromyalgia syndrome and other widespread pain conditions, in the rat. Firstly, rats exposed to unpredictable sound stress develop a delayed onset enhancement and prolongation of cytokine-induced mechanical hyperalgesia in muscle and skin. This unpredictable sound stress model in the rat demonstrates several features (cutaneous, musculoskeletal, and visceral hyperalgesia, as well as anxiety) that are found in patients with fibromyalgia syndrome. Thus, this model may be used to test hypotheses about the underlying mechanisms and response to therapy in patients with fibromyalgia (Green et al. J Pain 12:811-8, 2011). Secondly, we evaluated activity in nociceptors innervating the gastrocnemius muscle in rats exposed to water avoidance stress. This stressor, which produces mechanical hyperalgesia in skeletal muscle, decreased mechanical threshold of muscle nociceptors and markedly increased the number of action potentials and conduction velocity in nociceptor. Thirdly, we evaluated cutaneous and muscle nociception and activity in muscle nociceptors in an animal model of neonatal stress, limited bedding (NLB), in the rat. NLB treatment produced both mechanical muscle hyperalgesia (and prolonged hyperalgesia to prostaglandin), as well as lower threshold and increased conduction velocity in muscle nociceptors (Green et al., Pain 152:2549-56, 2011).
    As part of my Tobacco-Related Disease Program funded research, I investigated the sexually dimorphic effects of nicotine on key components of inflammation. I observed that in vivo administration of nicotine increases reactive oxygen species (ROS) production in neutrophils from both males and females. However, there is a sexually dimorphic adrenal medulla-dependence in this effect, since after adrenal medullectomy nicotine increases ROS generation in males but inhibits it in females. Chronic nicotine, inhibits ROS production in neutrophils from females, but has no effect in males. Chronic nicotine inhibited macrophage phagocytosis in females, but not males, an effect abolished by adrenal medullectomy, suggesting a dependence on an adrenal medulla factor. Chronic nicotine also markedly enhanced the ability of the inflammatory agent, bradykinin, to increase plasma extravasation component of inflammation, in females but not in males. These results (manuscripts in preparation) show that nicotine significantly affects several aspects of the inflammatory response, and some of these effects of nicotine exhibit sex differences, that may, at least in part, underlie the sex differences in the effects of smoking on chronic diseases.
    I am also continuing to investigate the influence of sexually dimorphic neuroendocrine pathways on the inflammatory response. Specifically, I have been investigating the effect of sex and sex steroids on role of the sympathoadrenal axis, which is activated by stress, on several components of inflammation viz. plasma protein extravasation, leukocyte recruitment, phagocytosis and reactive oxygen species generation. Since the adrenal medulla is a principal organ of the stress response, I have been assessing the effect of activation of stress axes by different forms of stress stimuli on the inflammatory response. This research has important implications since stress exacerbates signs and symptoms of inflammatory diseases in humans and in animal models. I have shown that both the duration and severity of stress differentially affects the inflammatory response, probably by differential activation of the stress axes. I have shown that there is a striking sexual dimorphism in the effect of stress on plasma extravasation in that non-habituating stress markedly enhances plasma protein extravasation in female rats (Green & Levine, Eur. J. Pharmacol, 2005). In my recent studies on leukocyte recruitment, I have shown that stress markedly enhanced neutrophil recruitment in male rats, but not in females (Barker et al., Br. J. Pharmcol. 2005). This effect is dependent on sex steroids and on an intact sympathoadrenal system. I have also studied the effect of sympathoadrenal modulation on human leukocyte function in has been investigated, in collaboration with colleagues. These studies have shown that there is a marked sexual dimorphism in ß2-adrenergic receptor binding (the receptor that binds the principal adrenal medulla-derived stress hormone, epinephrine) as well as in ß-adrenergic-stimulated non-directed locomotion (chemokinesis) (de Coupade et al., Br. J. Pharmacol. 2004). I have also shown the important role played by ß2-adrenergic receptors in leukocyte migration by employing ß2-adrenergic receptor knock-out mice (de Coupade et al., J. Neuroimmunol. 2005).


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    Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Researchers can login to make corrections and additions, or contact us for help.
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    1. Alvarez P, Green PG, Levine JD. Neonatal Handling Produces Sex Hormone-Dependent Resilience to Stress-Induced Muscle Hyperalgesia in Rats. J Pain. 2018 Feb 09. PMID: 29432863.
      View in: PubMed
    2. Alvarez P, Bogen O, Green PG, Levine JD. Nociceptor interleukin 10 receptor 1 is critical for muscle analgesia induced by repeated bouts of eccentric exercise in the rat. Pain. 2017 Aug; 158(8):1481-1488. PMID: 28628078.
      View in: PubMed
    3. Ferrari LF, Araldi D, Green P, Levine JD. Age-dependent sexual dimorphism in susceptibility to develop chronic pain in the rat. Neuroscience. 2017 Jul 01. PMID: 28676241.
      View in: PubMed
    4. Araldi D, Ferrari LF, Green P, Levine JD. Marked sexual dimorphism in 5-HT1 receptors mediating pronociceptive effects of sumatriptan. Neuroscience. 2017 Mar 06; 344:394-405. PMID: 28040566.
      View in: PubMed
    5. Niwa M, Aoki H, Hirata A, Tomita H, Green PG, Hara A. Retinal Cell Degeneration in Animal Models. Int J Mol Sci. 2016 Jan 15; 17(1). PMID: 26784179; PMCID: PMC4730351.
    6. Ferrari LF, Bogen O, Green P, Levine JD. Contribution of Piezo2 to endothelium-dependent pain. Mol Pain. 2015 Oct 24; 11:65. PMID: 26497944; PMCID: PMC4619430.
    7. Green PG, Alvarez P, Levine JD. Topical Tetrodotoxin Attenuates Photophobia Induced by Corneal Injury in the Rat. J Pain. 2015 Sep; 16(9):881-6. PMID: 26086898; PMCID: PMC4664153.
    8. Alvarez P, Levine JD, Green PG. Neonatal handling (resilience) attenuates water-avoidance stress induced enhancement of chronic mechanical hyperalgesia in the rat. Neurosci Lett. 2015 Mar 30; 591:207-11. PMID: 25637700; PMCID: PMC4711809.
    9. Joseph EK, Green PG, Levine JD. ATP release mechanisms of endothelial cell-mediated stimulus-dependent hyperalgesia. J Pain. 2014 Jul; 15(7):771-7. PMID: 24793242.
      View in: PubMed
    10. Chen X, Green PG, Levine JD. Does the antihyperalgesic disruptor of endothelial cells, octoxynol-9, alter nociceptor function? J Neurophysiol. 2014 Jul 15; 112(2):463-6. PMID: 24790171; PMCID: PMC4064416.
    11. Alvarez P, Green PG, Levine JD. Role for monocyte chemoattractant protein-1 in the induction of chronic muscle pain in the rat. Pain. 2014 Jun; 155(6):1161-7. PMID: 24637038; PMCID: PMC4303347.
    12. Reichling DB, Green PG, Levine JD. The fundamental unit of pain is the cell. Pain. 2013 Dec; 154 Suppl 1. PMID: 24347805.
      View in: PubMed
    13. Reichling DB, Green PG, Levine JD. The fundamental unit of pain is the cell. Pain. 2013 Dec; 154 Suppl 1:S2-9. PMID: 23711480.
      View in: PubMed
    14. Alvarez P, Green PG, Levine JD. Stress in the adult rat exacerbates muscle pain induced by early-life stress. Biol Psychiatry. 2013 Nov 01; 74(9):688-95. PMID: 23706525; PMCID: PMC3760993.
    15. Joseph EK, Green PG, Bogen O, Alvarez P, Levine JD. Vascular endothelial cells mediate mechanical stimulation-induced enhancement of endothelin hyperalgesia via activation of P2X2/3 receptors on nociceptors. J Neurosci. 2013 Feb 13; 33(7):2849-59. PMID: 23407944; PMCID: PMC3711399.
    16. Alvarez P, Chen X, Bogen O, Green PG, Levine JD. IB4(+) nociceptors mediate persistent muscle pain induced by GDNF. J Neurophysiol. 2012 Nov; 108(9):2545-53. PMID: 22914655; PMCID: PMC3545184.
    17. Parada CA, Tambeli CH, Green PG, Cairns BE. Primary afferent nociceptor as a target for the relief of pain. Pain Res Treat. 2012; 2012:348043. PMID: 22550578; PMCID: PMC3324912.
    18. Alvarez P, Gear RW, Green PG, Levine JD. IB4-saporin attenuates acute and eliminates chronic muscle pain in the rat. Exp Neurol. 2012 Feb; 233(2):859-65. PMID: 22206923; PMCID: PMC3272112.
    19. Green PG, Chen X, Alvarez P, Ferrari LF, Levine JD. Early-life stress produces muscle hyperalgesia and nociceptor sensitization in the adult rat. Pain. 2011 Nov; 152(11):2549-56. PMID: 21864980; PMCID: PMC3199316.
    20. Chen X, Green PG, Levine JD. Abnormal muscle afferent function in a model of Taxol chemotherapy-induced painful neuropathy. J Neurophysiol. 2011 Jul; 106(1):274-9. PMID: 21562188; PMCID: PMC3129739.
    21. Green PG, Alvarez P, Gear RW, Mendoza D, Levine JD. Further validation of a model of fibromyalgia syndrome in the rat. J Pain. 2011 Jul; 12(7):811-8. PMID: 21481648; PMCID: PMC3130888.
    22. Dina OA, Levine JD, Green PG. Enhanced cytokine-induced mechanical hyperalgesia in skeletal muscle produced by a novel mechanism in rats exposed to unpredictable sound stress. Eur J Pain. 2011 Sep; 15(8):796-800. PMID: 21419675; PMCID: PMC3123688.
    23. Chen X, Green PG, Levine JD. Neuropathic pain-like alterations in muscle nociceptor function associated with vibration-induced muscle pain. Pain. 2010 Nov; 151(2):460-6. PMID: 20800357; PMCID: PMC2932645.
    24. Alvarez P, Levine JD, Green PG. Eccentric exercise induces chronic alterations in musculoskeletal nociception in the rat. Eur J Neurosci. 2010 Sep; 32(5):819-25. PMID: 20726881; PMCID: PMC2974795.
    25. Dina OA, Joseph EK, Levine JD, Green PG. Mechanisms mediating vibration-induced chronic musculoskeletal pain analyzed in the rat. J Pain. 2010 Apr; 11(4):369-77. PMID: 19962353; PMCID: PMC2847637.
    26. Khasar SG, Dina OA, Green PG, Levine JD. Sound stress-induced long-term enhancement of mechanical hyperalgesia in rats is maintained by sympathoadrenal catecholamines. J Pain. 2009 Oct; 10(10):1073-7. PMID: 19576859; PMCID: PMC2757466.
    27. Brown AS, Levine JD, Green PG. Sexual dimorphism in the effect of sound stress on neutrophil function. J Neuroimmunol. 2008 Dec 15; 205(1-2):25-31. PMID: 18838177.
      View in: PubMed
    28. Dina OA, Khasar SG, Alessandri-Haber N, Bogen O, Chen X, Green PG, Reichling DB, Messing RO, Levine JD. Neurotoxic catecholamine metabolite in nociceptors contributes to painful peripheral neuropathy. Eur J Neurosci. 2008 Sep; 28(6):1180-90. PMID: 18783367; PMCID: PMC2746092.
    29. Khasar SG, Burkham J, Dina OA, Brown AS, Bogen O, Alessandri-Haber N, Green PG, Reichling DB, Levine JD. Stress induces a switch of intracellular signaling in sensory neurons in a model of generalized pain. J Neurosci. 2008 May 28; 28(22):5721-30. PMID: 18509033; PMCID: PMC2518401.
    30. Dina OA, Levine JD, Green PG. Muscle inflammation induces a protein kinase Cepsilon-dependent chronic-latent muscle pain. J Pain. 2008 May; 9(5):457-62. PMID: 18342576; PMCID: PMC2424185.
    31. Dina OA, Khasar SG, Alessandri-Haber N, Green PG, Messing RO, Levine JD. Alcohol-induced stress in painful alcoholic neuropathy. Eur J Neurosci. 2008 Jan; 27(1):83-92. PMID: 18093169.
      View in: PubMed
    32. de Coupade C, Brown AS, Dazin PF, Levine JD, Green PG. beta(2)-Adrenergic receptor-dependent sexual dimorphism for murine leukocyte migration. J Neuroimmunol. 2007 May; 186(1-2):54-62. PMID: 17442405; PMCID: PMC1994158.
    33. Summer GJ, Puntillo KA, Miaskowski C, Green PG, Levine JD. Burn injury pain: the continuing challenge. J Pain. 2007 Jul; 8(7):533-48. PMID: 17434800.
      View in: PubMed
    34. Summer GJ, Puntillo KA, Miaskowski C, Dina OA, Green PG, Levine JD. TrkA and PKC-epsilon in thermal burn-induced mechanical hyperalgesia in the rat. J Pain. 2006 Dec; 7(12):884-91. PMID: 17157774.
      View in: PubMed
    35. Levine JD, Khasar SG, Green PG. Neurogenic inflammation and arthritis. Ann N Y Acad Sci. 2006 Jun; 1069:155-67. PMID: 16855143.
      View in: PubMed
    36. Barker LA, Dazin PF, Levine JD, Green PG. Sympathoadrenal-dependent sexually dimorphic effect of nonhabituating stress on in vivo neutrophil recruitment in the rat. Br J Pharmacol. 2005 Aug; 145(7):872-9. PMID: 15912135; PMCID: PMC1576213.
    37. Khasar SG, Green PG, Levine JD. Repeated sound stress enhances inflammatory pain in the rat. Pain. 2005 Jul; 116(1-2):79-86. PMID: 15936144.
      View in: PubMed
    38. Khasar SG, Dina OA, Green PG, Levine JD. Estrogen regulates adrenal medullary function producing sexual dimorphism in nociceptive threshold and beta-adrenergic receptor-mediated hyperalgesia in the rat. Eur J Neurosci. 2005 Jun; 21(12):3379-86. PMID: 16026475.
      View in: PubMed
    39. Green PG. Gastrin-releasing peptide, substance P and cytokines in rheumatoid arthritis. Arthritis Res Ther. 2005; 7(3):111-3. PMID: 15899059; PMCID: PMC1174968.
    40. Green PG, Levine JD. Sexual dimorphism in the effect of nonhabituating stress on neurogenic plasma extravasation. Eur J Neurosci. 2005 Jan; 21(2):486-92. PMID: 15673447.
      View in: PubMed
    41. de Coupade C, Gear RW, Dazin PF, Sroussi HY, Green PG, Levine JD. Beta 2-adrenergic receptor regulation of human neutrophil function is sexually dimorphic. Br J Pharmacol. 2004 Dec; 143(8):1033-41. PMID: 15477226; PMCID: PMC1575953.
    42. Miao FJ, Green PG, Levine JD. Mechanosensitive duodenal afferents contribute to vagal modulation of inflammation in the rat. J Physiol. 2004 Jan 01; 554(Pt 1):227-35. PMID: 14678504; PMCID: PMC1664747.
    43. Miao FJ, Green P, Benowitz N, Levine JD. Vagal modulation of spinal nicotine-induced inhibition of the inflammatory response mediated by descending antinociceptive controls. Neuropharmacology. 2003 Oct; 45(5):605-11. PMID: 12941374.
      View in: PubMed
    44. Khasar SG, Miao FJ, Gear RW, Green PG, Levine JD. Vagal modulation of bradykinin-induced mechanical hyperalgesia in the female rat. J Pain. 2003 Jun; 4(5):278-83. PMID: 14622697.
      View in: PubMed
    45. Khasar SG, Green PG, Gear RW, Isenberg W, Levine JD. Gonadal hormones do not account for sexual dimorphism in vagal modulation of nociception in the rat. J Pain. 2003 May; 4(4):190-6. PMID: 14622703.
      View in: PubMed
    46. Khasar SG, Green PG, Miao FJ, Levine JD. Vagal modulation of nociception is mediated by adrenomedullary epinephrine in the rat. Eur J Neurosci. 2003 Feb; 17(4):909-15. PMID: 12603283.
      View in: PubMed
    47. Strausbaugh HJ, Green PG, Dallman MF, Levine JD. Repeated, non-habituating stress suppresses inflammatory plasma extravasation by a novel, sympathoadrenal dependent mechanism. Eur J Neurosci. 2003 Feb; 17(4):805-12. PMID: 12603270.
      View in: PubMed
    48. Khasar SG, Miao FJ, Gear RW, Green PG, Isenberg WM, Levine JD. Sympathetic-independent bradykinin mechanical hyperalgesia induced by subdiaphragmatic vagotomy in the rat. J Pain. 2002 Oct; 3(5):369-76. PMID: 14622740.
      View in: PubMed
    49. Schmidt BL, Tambeli CH, Barletta J, Luo L, Green P, Levine JD, Gear RW. Altered nucleus accumbens circuitry mediates pain-induced antinociception in morphine-tolerant rats. J Neurosci. 2002 Aug 01; 22(15):6773-80. PMID: 12151557.
      View in: PubMed
    50. Jasmin L, Tien D, Weinshenker D, Palmiter RD, Green PG, Janni G, Ohara PT. The NK1 receptor mediates both the hyperalgesia and the resistance to morphine in mice lacking noradrenaline. Proc Natl Acad Sci U S A. 2002 Jan 22; 99(2):1029-34. PMID: 11805341; PMCID: PMC117425.
    51. Green PG, Kitchen I, Crowder M. Interactions between anticholinesterase poisoning and opioid analgesia and locomotion in mice. Neurotoxicol Teratol. 1988 Jul-Aug; 10(4):315-9. PMID: 3147363.
      View in: PubMed
    52. Green PG, Kitchen I. Differential displacement of opioids from plasma protein binding sites by di-isopropylfluorophosphate in the mouse. J Pharm Pharmacol. 1988 Apr; 40(4):292-3. PMID: 2900315.
      View in: PubMed
    53. Green PG, Kitchen I. Antinociception opioids and the cholinergic system. Prog Neurobiol. 1986; 26(2):119-46. PMID: 3704168.
      View in: PubMed
    54. Kitchen I, Green PG. Differential effects of di-isopropylfluorophosphate poisoning and its treatment on opioid antinociception in the mouse. Life Sci. 1983; 33 Suppl 1:669-72. PMID: 6664242.
      View in: PubMed
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