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).