The Sympathetic Nervous System and Pain
Abstract and Keywords
This chapter reviews some of the preclinical studies of the sympathetic nervous system’s role in arthritis, inflammatory, and neuropathic pain, in light of the emerging understanding of how the immune system, sensory system, and sympathetic system markedly affect each other’s function, with many mechanisms besides sprouting. Many studies show a pro-inflammatory and pro-nociceptive role for the sympathetic nerves in preclinical models. However, these studies are sometimes conflicting, and the role of the sympathetic nerves can sometimes be anti-inflammatory or anti-nociceptive, particularly at later stages or when systemic effects on immune tissues are considered. The chapter discusses human correlates of these preclinical studies, as well as some possible reasons for the many conflicting studies in the literature. The chapter argues that sympathetic-based interventions for chronic pain conditions hold promise despite the conflicting findings in the field, especially if better ways to define appropriate subsets of patients can be developed.
In this chapter, we discuss some of the preclinical studies of sympathetic nervous system effects on pain, and how these correlate with clinical or human studies. One focus of the chapter will be on the interactions between the sympathetic nervous system and the immune system as they relate to pain. Some of the earliest preclinical studies of sympathetically regulated pain focused on sympathetic–sensory neuron interactions, and even recent clinically oriented studies often focus on this aspect (e.g., Liao, Tsauo, Liou, Chen, & Rau, 2016). However, the more recent understanding of the importance of interactions between the immune and sensory nervous systems on one hand (Foster, Seehus, Woolf, & Talbot, 2017), and interactions between the sympathetic and immune systems on the other (Jänig, 2014), leads us to propose that understanding sympathetic effects on the immune system will prove fruitful in understanding sympathetically regulated pain.
This chapter will focus primarily on studies in the peripheral nervous system; for a discussion of the larger feedback loops involving the brain as well as the peripheral nerves and immune system, the reader is referred to several recent reviews (Jänig, 2014; Koopman et al., 2011). Finally, we will suggest some possible reasons for the fact that the topic of sympathetically regulated pain has been contentious and sometimes contradictory, in both the preclinical and the clinical literature.
Aspects of Sympathetic Anatomy and Physiology Relevant to Pain
Basic textbook descriptions of the autonomic nervous system often emphasize the dual innervation of various structures by the sympathetic and parasympathetic nervous systems, usually with opposing effects. Hence, the sympathetic effects on structures such as the heart (increasing rate and force of contraction), iris (pupil dilation), and digestive tract (inhibition of peristalsis) are generally the opposites of the parasympathetic effects. However, in considering the role of the sympathetic system in pain, it is perhaps especially relevant to consider some of the targets and effects not generally emphasized in the basic textbook descriptions of the autonomic nervous system. Often, these targets lack parasympathetic innervation. An important example is the sympathetic innervation of primary and secondary immune tissues, which may indirectly affect pain (Figure 1).
Sympathetic innervation of primary immune organs (e.g., bone marrow, thymus) and secondary immune organs (e.g., lymph nodes, spleen, gut-associated lymphoid tissue) is characterized by close or even synaptic-like contacts between sympathetic nerve endings and immune cells (Bellinger & Lorton, 2014; Jänig, 2014; Takenaka, Guereschi, & Basso, 2017). It has been proposed that the sympathetic neurons regulating these immune tissues may form a functionally distinct pathway, with distinct regulation and reflex patterns, analogous to the distinct pathways of the subsets of sympathetic neurons that regulate vasoconstriction or sudomotor responses. For example, much of the sympathetic innervation of the spleen appears to be regulated differently than typical vasoconstrictor neurons are (Jänig, 2014).
Although our primary focus in this chapter is on the peripheral nervous system, a brief discussion of the control of the sympathetic nervous system by the central nervous system is in order. The sympathetic postganglionic neurons are controlled by cholinergic preganglionic neurons with cell bodies located in the intermediolateral zone of the thoracolumbar spinal cord; in the prevertebral ganglia, they can also receive direct connections from collateral axons of visceral sensory neurons. The postganglionic sympathetic cells are therefore the motor arm of spinal-level or local autonomic reflexes. In addition, these cells also are regulated by inputs from the brain stem and hypothalamus. This descending information, integrated with spinal-level autonomic reflexes, coordinates complex reflex patterns regulating autonomic functions, with the effect of maintaining homeostasis and responding to internal or external threats. Higher brain centers (cortical and limbic) also participate in regulating the sympathetic output; an example is the activation by psychological stressors. The afferent limb of these systemic autonomic reflexes includes not only sensory (especially visceral) nerves and enteric nerves, but also systemic hormones and other humoral messengers such as cytokines or blood glucose levels. Some of these circuits, such as those involved in cardiovascular regulation, osmoregulation, and regulation of body temperature, are well understood. (Jänig, 2013, 2014). The putative central circuit regulating immune function is not as well studied, although systemic cytokines are known to play a role in signaling between the immune system and brain centers involved in regulating the sympathetic output to immune tissues. However, some studies have demonstrated regulation of neurogenic inflammation and dorsal root reflexes by sympathetic neurons occurring at the spinal level and in the periphery (Lin, Zou, Fang, & Willis, 2003; Svennsson & Sorkin, 2017).
Most sympathetic fibers release noradrenaline (norepinephrine) as their transmitter, which regulates target tissues through two classes of adrenoreceptors (α and β). However, a number of co-transmitters have been identified, including adenosine triphosphate (ATP), vasoactive intestinal peptide (VIP), and nitric oxide, which may themselves function as immune modulators (Pongratz & Straub, 2014). Since both sensory neurons and immune cells may express receptors not only for noradrenaline, but for these co-transmitters, the existence of co-transmitters may be an important consideration in designing studies of sympathetic regulation of pain. In particular, sympathetic regulation of a particular pain phenotype cannot be ruled out simply by showing that adrenergic blockade has no effect. Conversely, under some conditions, cell types other than the sympathetic nerves (and the adrenal gland) may serve as sources of noradrenaline.
Systemic versus Local Effects of the Sympathetic Nervous System on Immunity
The functional consequences of the sympathetic innervation of immune tissues are still being elucidated. In many, but not all, cases, the overall effect, especially at the systemic level, seems to be to suppress immunity and inflammation, but these effects vary with context in a complex way (Pongratz & Straub, 2014), and localized sympathetic effects may be more pro-inflammatory (Elenkov, Wilder, Chrousos, & Vizi, 2000). An example of a more systemic effect is the sympathetic innervation of the spleen, which suppresses natural killer cell activity (Jänig, 2014). Sympathetic innervation of the bone marrow increases release of hematopoietic stem/progenitor cells, which can then migrate to sites of tissue injury and differentiate into anti-inflammatory (type 2) macrophages (Jung, Levesque, & Ruitenberg, 2017). Many immune cells express receptors for noradrenaline, the primary sympathetic transmitter. In several types of immune cells, activation of the β class of adrenergic receptors drives an anti-inflammatory or type-2 immune response, while stimulation of α class receptors drives a pro-inflammatory response (Bellinger & Lorton, 2014). This suggests that the net effect of sympathetic stimulation of immune tissue may depend on what receptors are present, which may vary in different pathological states. This also makes it more difficult to extrapolate from in vitro studies of adrenergic stimulation of immune cells to the in vivo situation.
A study of sympathetic effects on neuroinflammation in the dorsal root ganglia (DRG) evoked by peripheral nerve transection showed that, although local sympathetic denervation (removal of the lumbar sympathetic ganglia nearest the DRG) reduced immune cell infiltration in the DRG, a more limited, isolated denervation of only the draining lymph node increased T-cell infiltration in the DRG (McLachlan & Hu, 2014). We will discuss other examples of this type of finding, in which local sympathetic innervation of a non-immune tissue (the DRG, in this case) is pro-inflammatory, while innervation of the immune tissue suppresses immune function. Other studies of sympathetic innervation of the lymph node also found that it served to inhibit emigration of lymphocytes (Madden, 2017).
The sympathetic innervation of blood vessels may also have effects on immunity and inflammation, and hence on pain, not only through their regulation of blood flow, but through their effects on vascular permeability and on immune cell trafficking between blood and tissue. (Increased vascular permeability and plasma extravasation in response to sympathetic stimulation in joint blood vessels are discussed in the section on arthritis models.) Trafficking of immune cells across the endothelium into the tissues is regulated by intercellular adhesion molecules, whose expression is increased by sympathetic nerve activity. This effect contributes to increased immune cell recruitment during local inflammation (Mousa et al., 2010) and accounts for the circadian rhythm in recruitment (Scheiermann et al., 2012).
A final example of a “non-classical” sympathetic innervation is the presence of free sympathetic nerve fibers in, for example, the skin, joints (see following), and even on the surface of the DRG (Xie, Strong, & Zhang, 2010; see Figure 1). It has been proposed that sympathetic fibers in the skin that do not innervate “classical” targets such as arterioles and sweat glands may play a role in regulating immunity (Jänig, 2014). In general, the function of these fibers is poorly understood, but as discussed in greater detail later, they may have important modifying effects on pain.
Clinical Pain Conditions Treated by Sympathetic Interventions
The first description of pain related to sympathetic nervous system dysfunction was by Claude Bernard in 1851, describing what is today termed “complex regional pain syndrome” (CRPS). This condition is characterized by persistent pain and hyperalgesia in the affected limb, disproportionate to the initiating injury (or even in the absence of a known precipitating injury), along with signs of autonomic dysfunction such as vasomotor and sudomotor disturbances. It has been treated with some form of sympathetic blockade since the 1940s, and sympathetic blockade (induced either by injection of local anesthetic near the anatomically relevant sympathetic ganglia, or lesion of those ganglia) remains a recommended treatment (Harden et al., 2013). This is despite the fact that high-quality clinical trials proving (or disproving) the efficacy of such sympathetic blocks remain scarce (Harden et al., 2013; O’Connell et al., 2016). As with some other long-established clinical treatments, the lack of high-quality clinical trials may stem partly from the difficulties inherent in designing randomized blinded trials to test an already well-established and somewhat invasive treatment, and one that does not involve new drugs with patent protection. It is, however, better accepted that sympathetic blockade works better at earlier stages of CRPS than at late stages (AbuRahma, Robinson, Powell, Bastug, & Boland, 1994).
Other conditions that are sometimes treated with sympathetic blocks include phantom limb pain, herpes zoster and post-herpetic neuralgia, post-mastectomy pain, and cancer pain (Sekhadia, Nader, & Benzon, 2011). As with CRPS, high-quality controlled studies of efficacy are often lacking. Also similar to CRPS, some studies indicate that sympathetic blockade is more effective earlier in the course of herpes zoster (Kumar, Krone, & Mathieu, 2004).
Sympathetic blocks (via local anesthetic injections) are also used diagnostically to determine if a given patient’s pain is sympathetically maintained. However, a retrospective clinical study (Agarwal-Kozlowski, Lorke, Habermann, Schulte am Esch, & Beck, 2011) described reductions in chronic pain using a catheter approach to provide longer lasting sympathetic blockade than is achieved by the usual single injections. This study described 293 patients with intractable burning/stabbing pain from a number of causes (including 103 with post-herpetic neuralgia and 69 with CRPS). Median numerical rating pain scores decreased dramatically, from 8 to 2 in this study. Because pain relief often required more than a week of blockade, the authors noted that most patients would have been traditionally classified as having sympathetically independent pain.
Compounding the difficulty in obtaining rigorous clinical studies of sympathetic blockade, the rate of successful clinical blockade in one study of CRPS patients when strict criteria were applied was found to be less than 30% for blocks induced by injection of local anesthetic near the sympathetic ganglia, and many studies did not systematically evaluate the success of such injections (Harden et al., 2013). In addition, variability in sympathetic anatomy in humans and the existence of alternate pathways for sympathetic fibers to reach a particular anatomical region may also make it difficult ensure that a local sympathetic block has achieved the desired result (Hogan & Abram, 1997; Rocha Rde et al., 2014).
Preclinical Studies of Sympathetic Regulation of Pain, and Their Human Correlates
The role of the sympathetic nervous system has been examined in several different preclinical models of neuropathic and inflammatory pain. Experimental methods to disrupt the sympathetic system include short term pharmacological block, chemical lesion, and surgical removal of particular sympathetic ganglia.
Sympathetic sprouting has been one important focus of preclinical work on sympathetic regulation of pain. Normally, sympathetic fibers in the DRG are associated only with blood vessels. McLachlan et al. first described abnormal sprouting of sympathetic fibers into the DRG after sciatic nerve transection, including formation of basket-like structures wrapped around sensory neuron cell bodies (McLachlan, Jang, Devor, & Michaelis, 1993; see Figure 1). Later studies showed that such sprouting occurs in many commonly used animal pain models involving peripheral axon injury (Lee, Yoon, Chung, & Chung, 1998; Pertin, Allchorne, Beggah, Woolf, & Decosterd, 2007; Ramer & Bisby, 1997) and models in which there is no axon damage, but the DRG is locally inflamed (Xie et al., 2006) or compressed (Chien, Li, Li, Xie, & Zhang, 2005). Basket structures have also been observed in DRG from human neuropathic pain patients (Shinder et al., 1999). Sprouting may also occur in the skin and at peripheral nerve injury sites, providing additional possible sites of abnormal sensory–sympathetic coupling (Watkins & Maier, 2002). Nerve growth factor, transported from the periphery to the DRG, may play a role in sympathetic sprouting within the DRG (Davis, Albers, Seroogy, & Katz, 1994). Relatively few functional studies of such coupling have been done, but these generally show that the sympathetic effect on sensory neurons is excitatory (Ali et al., 2000; Burchiel, 1984; Devor, Jänig, & Michaelis, 1994; McLachlan et al., 1993; Watkins & Maier, 2002; Xie et al., 2010).
Pain behaviors in a number of rodent neuropathic and inflammatory pain models have been shown to be reduced by sympathectomy, although this literature is often contradictory (see later discussion; and Table I in Pertin et al., 2007). Poor correlation between pain and the timing and degree of sprouting led some to question whether sympathetic sprouting was functionally significant (Kim et al., 1999; Kuner & Flor, 2016).
Sensory neurons have been shown to upregulate their expression of adrenergic receptors (particularly α receptors) under pathological conditions, which would a priori tend to enhance effects of sympathetic sprouting. This has been observed, for example, immunohistochemically in DRG cell bodies after peripheral nerve lesions, including in non-axotomized neurons (Birder & Perl, 1999). Some studies have looked at the effects of sympathetic stimulation on sensory fiber activity, primarily in in vivo preparations. In their original paper describing sympathetic sprouting after sciatic nerve transection, McLachlan et al. (McLachlan et al., 1993) showed that a short burst of activity in sensory axons could be recorded with extracellular recording methods upon stimulation of the preganglionic sympathetic fibers in vivo. In the same model, it was shown that adrenergic agonists increased spontaneous firing from DRG neurons (Sato & Perl, 1991). Twenty percent of polymodal C-fibers from injured, but none from normal, nerve gave a low frequency discharge in response to sympathetic stimulation in a rabbit ear in vitro nerve preparation. Effects of sympathetic activation are not always excitatory, however; Michaelis et al. (Michaelis, Devor, & Jänig, 1996) showed that inhibitory effects predominated at time points later after the injury. Many researchers have reported increased sensitivity of DRG neurons to noradrenaline in nerve-injured animals, but it should be noted that the doses in these studies are often at µM and even mM levels, which might be seen only in a synaptic cleft (e.g., (Abdulla & Smith, 1997; Maruo et al., 2006; Petersen, Zhang, Zhang, & LaMotte, 1996). Upregulation under pathological conditions of adrenoreceptors on non-neuronal cells, including immune cells and keratinocytes, might also mediate sympathetic effects on sensory neurons due to their release of cytokines and other inflammatory mediators (Drummond, 2014; Watkins & Maier, 2002). Upregulation of adrenoreceptors in peripheral nerves and keratinocytes has also been observed in human CRPS patients (Finch, Drummond, Dawson, Phillips, & Drummond, 2014). In addition, injection of noradrenaline, which is not painful in normal human subjects, does cause pain in a subset of CRPS patients, as well as in patients with other pain conditions such as phantom limb pain and post-herpetic neuralgia (Drummond, 2014).
Sympathetic Role in Rheumatoid Arthritis Models
Joints are an example of a tissue with sympathetic but not parasympathetic innervation (Koopman et al., 2011). This innervation is substantial, with density comparable to the sensory innervation (Schaible & Straub, 2014). The roles of this sympathetic innervation have been studied in number of different preclinical models of rheumatoid arthritis. Such models include joint injection of inflammation-inducing substances such as complete Freund’s adjuvant (CFA) or yeast or bacteria cell wall preparations; induction of a systemic immune response to proteins present in the joint such as collagen or proteoglycan; and injection into the joint of an antigen to which the animal has been previously sensitized (Asquith, Miller, McInnes, & Liew, 2009; Bevaart, Vervoordeldonk, & Tak, 2010).
Activation of the sympathetic innervation restricts blood flow in the joints. These fibers can be activated by either mechanical or chemical noxious stimuli stimulation of the joint, in a reflex that is similar to that of the sympathetics innervating the muscle vasculature (Schaible & Straub, 2014). However, sympathetic fiber endings are not restricted to arteriole blood vessels (site of blood flow regulation), but are also seen around capillaries and in the surrounding tissue. The sympathetic innervation is required for the increase in blood vessel permeability (as measured by extravasation of Evans Blue bound to albumin) in response to acute bradykinin injection into the joint (a model of acute joint inflammation) (Jänig & Green, 2014). Interestingly, this effect was proposed to be independent of noradrenaline release. The sympathetic innervation also enhances movement of leukocytes across the capillary (Schaible & Straub, 2014).
Studies examining the role of the sympathetic innervation in several different arthritis models show that, in several models, the development of arthritis is markedly reduced by prior sympathectomy or pharmacological sympathetic blockade during the induction period. Sometimes conflicting results are found when the sympathetic blockade is initiated after arthritic inflammation is well established, but in some studies, intervention at a later time point had the opposite effect, with sympathetic blockade reducing the severity of the arthritis. The overall picture that emerges (with some exceptions) is one in which the pro-inflammatory influence of the sympathetic system seen during the early phase of the arthritis model evolves into a lack of influence or perhaps even an anti-inflammatory influence at later stages (Koopman et al., 2011; Schaible & Straub, 2014). Especially at early time points, arthritis models are also associated with increased sympathetic sprouting within the joint and over the adjacent skin (Ghilardi et al., 2012; Longo, Osikowicz, & Ribeiro-da-Silva, 2013). Later stages may also be characterized by a decrease in sympathetic innervation of the joints, both in animal models and in humans, although other cell types such as macrophages or fibroblasts may become new sources of noradrenaline (Koopman et al., 2011), including in humans (Capellino et al., 2010; Miller, Jüsten, Schölmerich, & Straub, 2000).
It should be noted that many of the preclinical studies referred to here about the role of the sympathetic system in arthritis models examined arthritis severity (e.g., degree of swelling; indices of joint inflammation and destruction) but did not examine pain behaviors. While it might seem obvious that more severe arthritis should lead to higher pain levels, this is not a foregone conclusion. For example, divergent effects on pain and arthritis severity were observed in interleukin-17 (IL-17) knockout mice that showed reduced pain behaviors but no change in arthritis severity in the antigen-induced arthritis model when compared to wildtype mice. This effect was possibly related to the presence of IL-17 receptors on sensory neurons (Ebbinghaus et al., 2017). In humans also, radiological findings or degree of swelling may not always correlate with the amount of pain reported. However, some preclinical studies of arthritis models also investigated pain behavior. For example, chemical sympathectomy reduced thermal and mechanical pain behaviors as well as arthritis severity in a mouse antigen-induced arthritis model (Ebbinghaus, Gajda, Boettger, Schaible, & Brauer, 2012), and reduced pain behaviors in a CFA (joint injection) model in rats (Longo et al., 2013). Reducing sympathetic sprouting with antibodies to nerve growth factor also reduced pain behaviors in this model, without affecting arthritis progression, joint vascularization, or macrophage infiltration, perhaps suggesting a more direct effect on pain per se of the sprouted fibers (Ghilardi et al., 2012).
The role of the sympathetic system in regulating arthritis severity is not completely understood. In a study using the antigen-induced arthritis model in mice, chemical sympathectomy reduced joint swelling and indices of inflammation in the knee joint (Ebbinghaus et al., 2012). Levels of several inflammatory cytokines produced by stimulated cells from lymph or spleen tissue were examined, and the predominant effect of sympathectomy was a marked reduction in IL-17, suggesting that this might be a key player in mediating effects of sympathectomy. However, in a follow-up study (Ebbinghaus et al., 2017), IL-17 knockout mice showed no reduction in arthritis severity, and the effect of sympathectomy on arthritis severity was preserved. Thus, the molecular mechanism of reduced joint inflammation following sympathectomy remains to be elucidated. In addition, in the earlier study that showed reduced antigen-induced inflammation after sympathectomy, the amount of inflammation induced by injection of the immune stimulator zymosan into the joint was unaffected. This suggests that sympathetic effects on inflammation differ depending on whether the inflammation is innate or antigen-induced. This may have broader significance for other types of pain models, depending on which category they fall into.
Sympathetic blockade is not routinely used as an arthritis treatment, although an early study suggested it might be useful (Levine, Fye, Heller, Basbaum, & Whiting-O’Keefe, 1986). However, some human studies suggest that the sympathetic nervous system is overactive relative to the parasympathetic in rheumatoid arthritis patients, and that the degree of overactivity correlates with pain. In addition, the disease can be exacerbated by stress (Adlan, Paton, Lip, Kitas, & Fisher, 2017; Koopman et al., 2011). In the rat antigen-induced arthritis model, measurement of cardiovascular parameters showed a shift towards a more sympathetic-dominated state. Interestingly, this shift, as well as pain behaviors and joint inflammation and destruction induced by the model, could be ameliorated by blocking tumor necrosis factor α (TNFα) at the spinal level. Systemic TNFα was much less effective or ineffective by comparison (Boettger et al., 2010).
We have confined the preceding discussion to models and studies of rheumatoid arthritis. However, it should be noted that osteoarthritis is potentially affected by the sympathetic innervation of the joints and various bone compartments. Sympathetic regulation of bone remodeling could affect disease progression and hence pain, for example. In addition, there is growing appreciation of inflammatory components in osteoarthritis, which in turn could be regulated by the sympathetic innervation of the joints and immune tissues (Grässel, 2014; Mantyh, 2014). However, to our knowledge, there are few preclinical studies of sympathetic regulation of osteoarthritis, particularly with regard to pain. A few human studies suggest a possible role for the sympathetic system in osteoarthritis. For example, in synovial tissue taken from human osteoarthritis patients undergoing knee replacement, a decrease in both sensory and sympathetic innervation was observed, depending on the degree of inflammation (Eitner, Pester, Nietzsche, Hofmann, & Schaible, 2013). Interestingly, a study of osteoarthritis patients taking antihypertensive drugs showed that use of β adrenergic blockers was associated with lower pain scores and less opioid use, compared to use of other classes of antihypertensives (Buskila, Gladman, Hannah, & Kahn, 1989).
Sympathetic Role in Other Inflammatory Pain Models
Low back pain conditions often include an element of local inflammation in the region of the DRG. Preclinical studies have shown that surgical sympathectomy (removal of lumbar sympathetic ganglia) reduced pain behaviors in several rat models of low back pain (Iwase et al., 2012; Murata, Olmarker, Takahashi, Takahashi, & Rydevik, 2006; Ogon et al., 2015). The Ogon et al. study (2015) also showed that pharmacological sympathetic blockade (α receptor antagonists injected around the DRG) was effective. These findings suggest that the sympathetic effects on pain may occur near the DRG. Other findings supporting this idea include the findings that sympathectomy also reduced hyperexcitability of sensory neurons (Iwase et al., 2012), and the finding that even a “microsympathectomy”—that is, cutting the two gray rami by which postganglionic sympathetic axons enter the L4 and L5 spinal nerve and L4/L5 DRG regions—was highly effective in reducing both pain behaviors and sensory neuron hyperexcitability in a low back pain model induced by locally inflaming the L5 DRG (Xie et al., 2016). In that study, microsympathectomy was also shown to mitigate the upregulation of type 1 pro-inflammatory cytokines and downregulation of type 2 anti-inflammatory cytokines induced in the DRG by the model. In addition (more relevant to the clinical situation), microsympathectomy was also shown to be effective in reducing established pain behaviors when performed two weeks after the DRG inflammation.
Models of peripheral inflammatory pain often involve injection into the rodent hindpaw of substances that induce inflammation (e.g., carrageenan, CFA) or tissue damage (e.g., formalin). These models result in mechanical and/or thermal hypersensitivity and allodynia, as well as spontaneous pain. Chemical or surgical (removal of lumbar sympathetic ganglia) sympathectomy reduced pain induced by bee venom injection into the paw (Chen, Qu, He, Wang, & Wen, 2010). Pain behaviors in the CFA model were markedly reduced by cutting the gray rami at the L4 and L5 DRGs prior to paw inflammation (Xie et al., 2016). In both of those studies, paw swelling was also reduced by sympathectomy, suggesting a role for reduced inflammation in mediating the sympathectomy effects. However, very different results were obtained in another study, also using the CFA model, in which neonatal chemical sympathectomy had almost no effect on behaviors (Woolf, Ma, Allchorne, & Poole, 1996). It seems likely that these conflicting findings may be related to the very different methods of sympathectomy used. The CFA model induces sprouting of sympathetic fibers into the upper dermis (Almarestani, Longo, & Ribeiro-da-Silva, 2008; Yen, Bennett, & Ribeiro-da-Silva, 2006), although this occurs relatively slowly. The sprouted fibers are associated with sensory nerve endings rather than blood vessels. Induction of pain behaviors was reduced by systemic pharmacological sympathetic blockade in a model of peripheral inflammatory pain induced by paw injection of bacterial endotoxin (Safieh-Garabedian et al., 2002). In this study, reduction of endotoxin-induced upregulation of several pro-inflammatory cytokines by sympathetic blockade was observed, also suggesting an immune-system related mechanism.
Neuropathic pain conditions are those arising from a disorder of the nervous system itself. Clinically, the neuropathic pain condition CRPS was one of the earliest to be treated with sympathetic blockade (see previous discussion). One of the earliest pain models in which sympathetic dependence of pain was characterized was the spinal nerve ligation model (Kim & Chung, 1992). In this model, the spinal nerves from the L5 or L5 plus L6 DRG are ligated. This model induces sympathetic sprouting within the DRG, and pain behaviors were markedly reduced in this model by surgical lumbar sympathectomy in early studies by the laboratory that originated the model (Choi, Yoon, Na, Kim, & Chung, 1994; Kim, Na, Sheen, & Chung, 1993). Pain behaviors can also be reduced by the microsympathectomy technique: that is, cutting only the gray rami to the L4 and/or L5 DRG (Kinnman & Levine, 1995; Xie et al., 2010). However, studies in this model have been controversial, with other groups finding no effect of sympathectomy (e.g., Ringkamp et al., 1999). Intriguingly, one group proposed that the magnitude of the effect of sympathectomy on pain behaviors in the spinal nerve ligation model may have been reduced when they were required to switch to specific pathogen-free rats (Xie, Park, Chung, & Chung, 2001). This would also support an immunological explanation for some of the great variability in experimental findings among different studies of sympathetic effects on the spinal nerve ligation model. More generally, insofar as sympathetic regulation of pain is mediated in part by immune mechanisms, researchers will need to be mindful of recent studies suggesting that recent adoption of specific pathogen-free husbandry practices may distort the normally occurring innate and adaptive immune responses, causing them to be immature in comparison to the immune response in animals harboring normally occurring microorganisms that that do not normally cause disease, or in animals that have cleared an infection (Tao & Reese, 2017).
A study using the spared nerve injury model, in which the nerve transection is much further from the DRG, observed only minor and delayed effects of neonatal chemical sympathectomy on pain behaviors (Pertin et al., 2007). Those authors interpreted their findings in terms of sympathetic sprouting, and concluded that pain behaviors in models with more remote axon injuries were less sensitive to sympathetic blockade, especially mechanical pain behaviors. In light of more recent findings about sympathetic regulation of inflammation, it is also feasible that the spinal nerve ligation model is more sensitive to sympathectomy in most studies because the injury, though considered “neuropathic” because nerves are transected, also induces a great deal of inflammation in the nearby DRG (Xie et al., 2010). Indeed, the gene-expression changes induced by DRG inflammation (without any nerve transection) much more closely resemble those observed in the spinal nerve ligation model than those observed in neuropathic pain models with more distal nerve injuries (Strong, Xie, Coyle, & Zhang, 2012).
Other preclinical models of neuropathic pain have also shown sometimes conflicting effects of sympathectomy on pain behaviors (Pertin et al., 2007). For example, mechanical and thermal pain behaviors induced by chronic constriction of the sciatic nerve, an early model of neuropathic pain induced by partial nerve injury (Bennett & Xie, 1988), showed varying degrees of inhibition by sympathectomy in different studies (Desmeules, Kayser, Weil-Fuggaza, Bertrand, & Guilbaud, 1995; Kim, Yoon, & Chung, 1997; Neil, Attal, & Guilbaud, 1991); results also varied depending on whether thermal, mechanical, or spontaneous pain was being measured.
Although pain models are conventionally characterized as neuropathic (involving damage to the nerves) or inflammatory, it is now recognized that neuropathic injuries always include a component that might be termed “inflammatory.” These include tissue repair mechanisms that involve immune cell infiltration and activation, and activation of microglia in the spinal cord and satellite glia in the DRG (Moalem & Tracey, 2006). Hence, some of the discussion in the section on inflammatory pain models may conceivably pertain to neuropathic pain models. In humans, the neuropathic pain condition CRPS clearly has inflammatory and immune components, including upregulation of pro-inflammatory cytokines, increased neurogenic inflammation, and in some cases, auto-antibody production (Schlereth, Drummond, & Birklein, 2014). Because CRPS most often develops after a limb fracture, a rat model based on distal tibial fracture and casting has been developed, which mimics elements of early CRPS, including mechanical pain, edema, limb warmth, and bone changes (Guo, Offley, Boyd, Jacobs, & Kingery, 2004). In this model, chemical sympathectomy (implemented after the model was established) reduced mechanical pain and indicators of inflammation. The pro-inflammatory cytokine interleukin-6 (IL-6) was reduced in the paw skin, but not several other inflammatory mediators whose expression had previously been shown to depend on sensory neurons. Keratinocytes expressing increased levels of adrenergic receptors in response to noradrenaline were proposed to be a primary source of the increased IL-6. Systemic blockade of adrenergic (β2) receptors also reduced pain behaviors in this model (Li et al., 2013). In view of the multiple possible sites of action of systemic sympathetic agents, it is noteworthy that this study also demonstrated mechanical pain and IL-6 production after acute paw injection of β2 receptor agonists into the hindpaw in naïve rats, supporting the interpretation that local sympathetic effects were important. Unlike other neuropathic pain models discussed, there seems to be less controversy about the role of the sympathetic nervous system in this rat CRPS model, although it has been noted that it does not model late-stage CRPS symptoms, for which in the clinical case, sympathetic interventions are less robust (Schlereth et al., 2014). A mouse version of this model has also been described (Guo et al., 2012) but to our knowledge has not yet been used to examine the role of the sympathetic system.
Possible Reasons for Discrepancies in Preclinical and Clinical Literature on the Effect of the Sympathetic Nervous System in Pain
As discussed before, there are often conflicting results in both preclinical and clinical literature about the role of the sympathetic nervous system in pain. Following, we discuss several possible factors that may contribute to this variability.
• A common theme in clinical and preclinical literature is that the timing of a sympathetic intervention determines its effect on pain. More specifically, the sympathetic nervous system often has a pro-nociceptive role earlier in the disease, which may disappear or become anti-nociceptive at later stages. In human patients, it is plausible that equivocal findings regarding sympathetic interventions may be because there are subsets of responsive and unresponsive patients that are at different stages of disease progression. In light of the local pro-inflammatory role played by sympathetic activation in many studies, effectiveness of sympathetic interventions might also vary depending on the degree of inflammation present in a particular patient. For example, a study (Alexander, Peterlin, Perreault, Grothusen, & Schwartzman, 2012) that measured plasma levels of several cytokines and soluble cytokine receptors found that CRPS patients fell into two clusters. About 32% of patients had a much more pro-inflammatory profile, significantly different from healthy controls’, while the rest did not differ significantly from controls. Overall, CRPS patients had approximately two-fold differences from controls in numerous inflammatory markers, but this was driven entirely by much larger-fold differences in the smaller cluster of patients only. Importantly, other clinical variables did not predict which cluster a patient belonged to, suggesting that differing degrees of inflammation can occur with similar clinical presentation.
• Global sympathectomy may give different results than more local methods of sympathectomy do. Because in many tissues the local sympathetic innervation seems to play a pro-inflammatory role, while sympathetic innervation of primary and secondary immune organs often has an anti-inflammatory or type-2 inflammation-skewing influence, it is likely that different effects on pain could be observed, depending on the method of sympathectomy. For example, localized denervation by cutting a few gray rami at the lumbar level, which was strongly anti-nociceptive in several pain models, might give different results than global sympathectomy using agents such as systemic injection of guanethidine or 6-hydroxy-dopamine. This is plausible because the more global sympathectomy methods might also evoke counteracting pro-inflammatory responses due to loss of innervation of immune tissue. Some chemical methods of sympathectomy may also affect non-neuronal cells that produce norepinephrine, in addition to the targeted sympathetic nerves (Madden, 2017; Pongratz & Straub, 2014). Lumbar surgical sympathectomy will denervate more structures than localized sympathectomy, but fewer structures than chemical sympathectomy. In addition, interpretation of experiments using systemic pharmacological blockers such as α or β adrenergic blockers, is confounded by the fact that receptor expression on sensory neurons and immune cells may change with disease or disease model, and by the fact that sympathetic nerves express various co-transmitters. It would be interesting to improve experimental methods of highly localized sympathectomy that could be applied to structures such as individual joints, bone regions, or muscles, to clarify the sympathetic role in pain models related to these structures. Some such methods have been described in other tissues (e.g., localized injection of guanethidine; Demas & Bartness, 2001) or dopamine β-hydroxylase antibody conjugated to saporin (Hayashida, Peters, Gutierrez, & Eisenach, 2012), though these have not always proved reproducible across species (Harris, 2012).
• Saturation effects in pain models used may obscure sympathetic effects. For example, mechanical pain in several of the neuropathic and inflammatory pain models mentioned almost reaches a floor value, which would make it difficult to show that a sympathetic innervation was further increasing pain. In the bradykinin-induced extravasation model of acute joint inflammation, sympathectomy could only reduce extravasation over a certain range of bradykinin concentrations; extravasation saturated at the same highest value, with or without sympathectomy (Jänig & Green, 2014). Hence studies using higher concentrations of bradykinin that concluded that sympathectomy has no effect may have simply been conducted in this saturated portion of the dose–response curve (Schaible & Straub, 2014).
• An issue that has received relatively little attention is the possible modification of the sympathetic nerves by inflammation or nerve damage. A few studies have observed signs of neuroinflammation or hyperexcitability in the sympathetic ganglia in response to peripheral nerve damage or peripheral inflammation (e.g., Hu & McLachlan, 2004; Li, Zhang, Xie, Strong, & Zhang, 2017). Given the long-held view that sympathetic postganglionic fibers are only activated by the preganglionic fibers, and the classic studies showing that axotomized sympathetic postganglionic fibers lose their preganglionic inputs via synaptic stripping (Purves, 1975), it is not clear how blockade or removal of already axotomized sympathetic endings can further affect pain and inflammation. However, it is worth noting that spontaneous activity of sympathetic neurons has been observed in a systemic inflammation model (Lukewich & Lomax, 2015) and an intestinal inflammation model (Dong, Thacker, Pontell, Furness, & Nurgali, 2008). In addition, effects of sympathectomy on bradykinin-induced plasma extravasation in joints are not mimicked by cutting the preganglionic fibers (Jänig & Green, 2014), suggesting that either activity in the sympathetic fibers is not required for the sympathetic regulation of extravasation, or the assumption that activity in postganglionic fibers only follows preganglionic activity is incorrect in some conditions. These examples suggest that studies of the effects of pain models and inflammation on the sympathetic system are needed to fully understand effects of the sympathetic system on pain and inflammation.
• Some clinical studies may have failed to see an effect of sympathetic blockade because they did not evaluate the effectiveness of the block, or because it was not long enough. Previously, we discussed the retrospective study (Agarwal-Kozlowski et al., 2011) showing dramatic improvements in patients with refractory chronic pain conditions, following prolonged sympathetic blockade with catheter methods. We think that this study is underappreciated, and it indicates to us that sympathetic interventions for pain may have profound clinical relevance, and that future clinical studies should focus on discovering how to identify which subgroups of patients may benefit from sympathetic blockade.
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