“More quality research has been performed on spinal manipulation than any other treatment of low back pain.” –THE SPINE JOURNAL
“There is moderate- to high-quality evidence that subjects with chronic neck pain...show clinically important improvements from a course of spinal manipulation or mobilization at 6, 12, and up to 104 weeks post treatment..” –JOURNAL OF MANIPULATIVE AND PHYSIOLOGICAL THERAPEUTICS
“Manual therapy (spinal mobilisation) is more effective and less costly for treating neck pain than physiotherapy or care by a general practitioner.”- THE BRITISH MEDICAL JOURNAL
“By every test of cost and effectiveness, the general weight of evidence shows chiropractic to provide important therapeutic benefits, at economical costs.” – ONTARIO’S MINISTRY OF HEALTH
“In patients with chronic spinal pain, manipulation, if not contraindicated, results in greater short-term improvement than acupuncture or medication.” - SPINE
“Manipulation alone improves back function in both the short and long terms, as does manipulation followed by exercise. “ – THE BRITISH MEDICAL JOURNAL
Overview of Dr. Spurgin's research project at UC Riverside
BACKGROUND:The HSA-axis consists of PVN projectionsto the ventrolateral medulla (VLM) where sympathetic preganglionic neurons project via the splanchnic nerve to adrenal chromaffin cells[35-40].During stress, much of the sympathoexcitatory output from the hypothalamus projects via the ventrolateral medulla (VLM)[41, 42].The rostral VLM contains premotor neurons controlling vasomotor tone, cardiac function, and is a major site for integration of descending influences and medullary reflexes controlling circulation. projections drive cardiovascular responses and provide autonomic drive to the kidneys, influencing heart rate and blood pressure[43, 44].Reticulospinal cardiovascular neurons in the C1 area of the VLM are catecholaminergic and project directly to preganglionic sympathetic neurons in the intermediolateral spinal column. C1 projections drive the activity ofadrenal chromaffin cells via the splanchnic nerve[35-40]. Both acetylcholine (ACh)[41, 45]and PACAP[40, 46]are synthesized by sympathoexcitatory C1 neurons and appear to work togethercentrallyto increase BP and HR, respectively. They also work to dramatically increase CA output by the adrenal via splanchnic nerve activity[47-49].
The relative contribution of ACh and PACAP to CA release depends on the degree of splanchnic nerve activity.ACh predominates during high neuronal activity[50, 51].Endogenous PACAP is released by direct splanchnic nerve stimulation in isolated, perfused adrenal glands during low frequency neuronal activity reminiscent of chronic mild stress[50, 51].PACAP may also contribute to the persistent effects of chronic stress, since PACAP-induced CA release[52-54]lasts much longer than release mediated by mixed muscarinic/nicotinic ACh signaling even though both are metabotropic[50, 55-58]. Indeed,PACAP signaling in the VLM participates in the resting HR of spontaneously hypertensive rats.PACAP belongs to the vasoactive intestinal peptide(VIP)/secretin/glucagon family of neuropeptide hormones.PACAP receptors G-protein coupled; the most abundant PACAP receptor is PAC1R which has much greater affinity for PACAP than VIP[52-54].
A recent report by May and colleagues indicates that the PACAP/PAC1 receptor system may be a key participant in chronic stress physiology. PTSD symptoms correlated significantly with plasma levels of PACAP38, the most predominant form of PACAP and also with a single and a singlenucleotide polymorphisms (SNPs) spanning thePAC1 receptor gene .PACAP is a potent secretagogue of CRH[3, 4, 60]and AVP[47, 61-63]andhas been implicated in prolonged (but not acute) HPA responses during chronic stress.Chronic stress also appears to cause a gradual shift in the balance of CRH to AVP drive within the HPA-axis.For example, following chronic restraint or chronic adjuvant arthritis stress, AVP gene transcription is maintained in PVN parvocellular neurons while CRH gene transcription becomes desensitized[64, 65]]. Social defeat or forced swimming stress are associated with elevations in basal and stimulated AVP levels in the PVN[66-68]that can are sustained for >30 min after stress exposure.Moreover, AVP (but not CRH or oxytocin) is markedly over-expressed in the PVN of rats bred for high anxiety-related behavior (HAB) relative to low anxiety-related behavior (LAB) rats.Interestingly, antidepressant therapy normalizes AVP over-expression in the PVN.In combination, these data point towards a significant role of AVP in chronic stress.
PACAP-dependent mechanisms sustain sympathoadrenal responses to prolonged but not acute stress. Evidence supports a role of PACAP in central and peripheral stress responses associated with HAS and HPA axes [1,4]. Deletion of the PACAP gene blunts stress-induced expression of c-Fos, an immediate early gene used as a marker of cell activation, in the medial amygdala and PVN. The participation of PACAP in chronic stress parallels that of AVP, which becomes increasingly more important than CRH, lending support to the idea that PACAP regulates chronic stress responses in a AVP-dependent manner[25, 64, 71]. However, it is unclear if the effect of PACAP on HPA responses is mediated through AVP.We have demonstrated that PACAP signaling is required for AVP release from magnocellular neuroendocrine cells of the hypothalamic supraoptic nucleus in response to hyperosmotic stimulation . Preliminary findings from a collaborative study with Dr. J. Waschek indicate that PACAP knockout mice display altered AVP responses to hyperosmotic stress . Pilot data from our lab indicates that PACAP can also stimulate AVP release from PVN punches in vitro (Fig. 3). These findings provide the background for the proposed studies designed to explore whether PACAP participates in AVP responses within the PVN and whether PACAP signaling is accentuated in chronic stress animals.
Massage therapy shows promise as a viable treatment for managing the harmful effects of chronic stress.Massage can positively affect behavioral manifestations of stress such as anxiety and depression[72, 73]. In humans, massage decreases heart rate and blood pressure while increasing vagal afferent activity as measured by heart-rate variability[30, 74].Massage has been shown to decrease plasma, urinary, and salivary cortisol[72, 75-78]and urinary CRH-like immunoreactivity.In rats, massage-like stroking of the abdomen has been shown to reduce BP and heart rate[29, 31, 32], and enhance feedback inhibition of the HPA axis by increasing glucocorticoid receptor gene expression.Massage increases EEG delta activity and decreases alpha and beta activity, suggesting a relaxation response.
In humans, the two most consistent variables that appear to be impacted by massage therapy are increased parasympathetic nerve activity and decreased salivary cortisol[31, 77]. The mechanisms underlying massage therapy impacts on these markers are poorly understood; however, it is likely that massage therapy drives PVN responses via a subcortical reflex arcthat involves dermal baroreceptor afferents from the vagus nerve via the nucleus of the solitary tract (NTS) and from spinal nerves via the dorsal horn[30, 81, 82].The PVN subsequently impacts heart rate and blood pressure via pre-parasympathetic projections to the dorsal motor nucleus of the vagus (DMNV)and via pre-sympathetic projections to the VLM and IML[41, 42].The proposed studies will examine if massage therapy can significantly reduce BP and HR responses to chronic stress and associated molecular changes, specifically increase activity markers for the parasympathetic arm of this response. Massage may decrease cortisolby means of a relaxation response involving cortical inhibition of the PVN via the medial prefrontal cortex and ventral subiculum.During our pilot studies involving massage in rats, animals appear to grow accustomed to the treatment after several applications. They appear to be quite relaxed during treatment and we expect that they may show physiological signs of cortical inhibition via decreased HPA-axis activity.
SIGNIFICANCE:Chronic stress has been shown to be a contributing factor for a variety of disorders such as hypertension, depression, fibromyalgia, and chronic regional pain syndrome[24, 85-93].The widespread prevalence of stress-related disorders is astounding.Recent estimates suggest that fibromyalgia alone affects approximately 1 in 20 women and nearly 5 million adults in the United States; major depression is the leading cause of disability worldwide; and nearly 31% of U.S. adults have high blood pressureresulting in an annual cost of ~$76.6 billion in health care services/missed work.
The effects of chronic stress are manifest via parallel activation of the hypothalamo–pituitary–adrenocortical (HPA)[18-20]and hypothalamo–sympatho–adrenal (HSA)[21-23]axes.Several recent articles have focused on the role of pituitary adenylate cyclase-activating polypeptide (PACAP) as a key player in both of these neuroendocrine stress circuits[1, 4, 5, 7].A recent review by Stroth et alnoted that PACAP “deserves further attention as a major multilevel stress regulator whose modulation could affect deleterious sustained stress while leaving intact the acute (fight or flight) stress response helpful for survival.”Studying PACAP’s role in sustained stress responses could provide support for PACAP as a novel therapeutic target in the treatment of stress related disorders.This approach has particular significance given recent findings that confirm an association betweenPACAP signalingand bothpost-traumatic stress disorderand major depression.
Importantly, massage therapy could prove to be a valuable tool in thepreventionof stress-related disorders.Consider, for instance, that nearly 1 in 5 soldiers returning from Iraq and Afghanistan suffer from post-traumatic stress with an estimated societal cost of ~$4-6 billion.Combat-deployed soldiers also exhibit higher incidences of hypertensionand chronic fatigue syndrome.In this context, a stress prevention strategy that includes massage therapy could be incredibly valuable.Further, if a preventive strategy is to be broadly employed, safety is of vital importance.Unlike other prophylactic measures that have been examined (e.g. alcohol, hydrocortisone, propranolol, and morphine), negative side effects from massage therapy are exceedingly rare.
INNOVATION:A few months ago, Stroth et alpublished the first review that highlighted PACAP as a major player in chronic stress responses within both the HSA and HPA-axes.Their paper presented evidencethatchronic stress and acute “emergency” stress may activate HPA and HAS axes via complementary pathways. PACAP appears to participate insustained stress responses as opposed to acute stress responses; for instance, in the HSA axis PACAP and acetylcholine (ACh) work in concert to stimulate CA release[47-49].ACh mediates CA secretion during high neuronal activity (e.g. acute “emergency” stress), while non-cholinergic signaling predominates during low neuronal activity (e.g. homeostatic functioning)[50, 51].A similar dichotomy is present in the HPA axiswhere hypothalamic responses to acute stress are driven by glutamate and GABA signaling whereas prolonged responses appear to involve PACAP signaling.The participation of PACAP in chronic stress parallels that of AVP, which becomes increasingly more important than CRH, lending support to the idea that PACAP regulates chronic stress responses in a AVP-dependent manner[25, 64, 71].In addition, there appears to be a shift in the balance between CRH and AVP drive during chronic stress.
The key innovation of our proposal expands upon this concept by introducing the hypothesis that responses to chronic mild stress preferentially involve “homeostatic” mechanisms as opposed to “emergency” mechanisms.There is evidence that PACAP is involved in basal homeostatic signaling; and, plasticity in autonomic circuits occurs when pathways are primed by homeostatic challenges to respond more effectively to subsequent stressors.We hypothesize, therefore, that diseases linked to chronic stress are due to agradual “ramping-up” ofhomeostatic PACAP signaling in both the HPA and HSA-axes which results in elevated basal activity in both systems.We propose that this may be a critical mechanism underlying the “exhaustion” stage of Hans Selye’s general adaptation syndrome.
In order to test our hypothesis, we have chosen psychological stressors that have never before been compared to one another.As a model for chronicmildstress, we are employing a sound stress protocol[100, 101].Chronic sound stress results in prolonged activation of both HSA[101, 102]and HPA axis activity[102-106]and has been shown to elevate blood pressure in rats.For chronicmoderatestress, we will utilize psychosocial intruder stress for which similar evidence exists.Intruder stress has been shown to influence plasma and adrenal CA levels, increase adrenal CA biosynthetic enzymes[108-114], elevate blood pressure[110, 115-118], and increase HPA axis activity[119-121].These stressors are also advantageous in that neither stressor is painful or physically demanding for the animals (as opposed to restraint, forced-swim, saline injection, etc.).
A further innovation in our proposal is the use of an animal model of massage therapy.We have used a modified version of the protocol employed by our collaborator Dr. M. Kurosawa and his associates[29, 32]to show decreased blood pressure and heart rate in control rats. We intend to use a similar protocol to demonstrate that massage therapy may be able to significantly reduce cardiovascular hyperactivity and other stress responses within the HPA and HAS. Moreover, we will explore whether massage can increase parasympathetic activity within the brainstem during periods of chronic stress.