Descending Pain Pathways Research Articles

Possible role for glutamic acid decarboxylase in fibromyalgia symptoms: A conceptual model for chronic pain

Fibromyalgia (FM) is a condition of chronic generalized musculoskeletal pain that is thought to be a disorder of central pain sensitization. A number of neurotransmitters in the ascending and descending pain pathways have been implicated in FM including glutamate and GABA. Glutamic acid decarboxylase (GAD) is the rate-limiting enzyme in the conversion of glutamate to GABA and decreased expression or activity of this enzyme could result in an imbalance of excitatory and inhibitory neurotransmission in the ascending and descending pain pathways. Specifically, the expression and activity of the predominant isoform of GAD (GAD65) is influenced by several factors that are associated with FM such as female sex, poor diet, obesity, sedentary lifestyle, and stress. We hypothesize that decreased GAD expression and/or activity plays a role in the development and exacerbation of FM leading to impairments in the three common domains of FM symptomatology: increased pain (hyperalgesia and allodynia), disrupted sleep, and disturbances in mood (anxiety and depression). There are several lines of evidence that appear to support a role of GAD in FM. First, the defining symptom of FM is pain and GAD65 knockout mice have been shown to exhibit supraspinal hyperalgesia. Second, GAD has been implicated in disorders of muscle stiffness and rigidity and morning stiffness is a common symptom of FM. Third, stress, depression, and anxiety, which are often comorbid with FM, decrease GAD activity. Fourth, FM is associated with poor sleep, specifically disrupted non-rapid eye movement (NREM) sleep, and the pharmacological induction of NREM sleep is associated with the activation of GAD-containing neurons in the preoptic hypothalamus. Fifth, FM is more commonly diagnosed in women than men and the activity of GAD is reduced by low levels of its cofactor pyroxidine, which is less well-absorbed by women and can be further lowered by diet, tobacco, and alcohol intake. Sixth, FM patients tend to be overweight or obese and caloric restriction and exercise have been shown to increase GAD expression and activity. These six general lines of evidence suggest that GAD expression and/or activity might underlie the pathophysiology of FM. If this hypothesis is supported by future empirical studies, our understanding of the etiology of FM could be greatly improved. Moreover, behavioral and pharmacological therapies that modulate or mimic the effects of GAD might hold promise for the treatment of this debilitating and poorly understood disorder.

Changes in serotoninergic and noradrenergic descending pain pathways during painful diabetic neuropathy: The preventive action of IGF1

Painful diabetic neuropathy (PDN) induces neuronal hyperactivity at the spinal cord and periaqueductal gray (PAG), a key area in descending nociceptive modulation. Since the PAG uses relay stations at serotoninergic and noradrenergic brainstem areas, we determined the serotonin and noradrenaline levels at the spinal cord of streptozotocin-diabetic rats and at those brainstem areas (serotoninergic rostroventromedial medulla and noradrenergic A5 and A7 cell groups). Since, during diabetes, the levels of insulin growth factor 1 (IGF1) decrease, reducing its neurotrophic effect in the brain, we also studied the effects of IGF1 treatment. One week after diabetes induction, subcutaneous injections of IGF1 (2.5mg/kg) were performed during 3weeks. Body weights, glycemia, and mechanical nociception were weekly evaluated until the end of the study, the time when the animals were subjected to a modified formalin test to study chemical allodynia. Serotonin and noradrenaline levels were quantified by ELISA at the spinal cord, whereas at the brainstem, the quantification was performed by immunohistochemistry against, respectively, tryptophan hydroxylase (TpH) or tyrosine hydroxylase (TH). STZ-diabetic rats exhibited mechanical hyperalgesia and chemical allodynia, along with higher spinal levels of serotonin and noradrenaline and higher numbers of neurons expressing TpH at the RVM and TH at the A5 noradrenergic cell group. Treatment with IGF1 prevented the behavioral signs of PDN and reversed the neuronal hyperactivity at the spinal cord and ventrolateral PAG and the neurochemical changes at the spinal cord and at the brainstem. Based on the facilitatory role of serotoninergic and noradrenergic descending modulation during chronic pain, the increased serotonin and noradrenaline innervation of the dorsal horn in STZ-diabetic rats may probably account for enhanced pain during PDN. The benefits of IGF1 in PDN are probably due to blockade of the increased peripheral input to the somatosensory system, but direct central actions cannot be discarded. The value of IGF1 in PDN treatment deserves further evaluation.

Fibromyalgia Syndrome: Practical Strategies for Improving Diagnosis and Patient Outcomes

Recent advances in the understanding of the etiology, epidemiology, diagnosis, and treatment of fibromyalgia must be applied in clinical practice to achieve optimal patient outcomes. Current evidence indicates that fibromyalgia is a hyperalgesic state, resulting from a generalized problem with augmented pain processing that likely results from the way the spinal cord and the brain process pain and other sensory information. The descending pain pathway involving serotonin, norepinephrine, and dopamine, as opposed to the descending opioid pain pathway, appears to be selectively attenuated. Newer treatment options targeted at the pain mechanisms include the alpha(2)-delta pregabalin, which binds to the alpha(2)-delta subunit of voltage-gated calcium channels in neurons, and the serotonin-norepinephrine dual reuptake inhibitors duloxetine and milnacipran. The US Food and Drug Administration (FDA) has approved pregabalin, duloxetine, and milnacipran for the management of fibromyalgia. In addition to pharmacologic therapy, patient education, cognitive behavioral therapy, aerobic exercise, and strength and flexibility training are important components of care. An individualized treatment plan should be developed with consideration of each patient's unique combination of fibromyalgia symptoms, functional level, and the presence of the comorbid psychiatric and medical conditions that are common in patients with fibromyalgia. This educational activity provides clinicians with the tools necessary to differentiate fibromyalgia syndrome from other chronic pain conditions through a review of recent clinical data and an application of an advanced understanding of pain pathways. Strategies to manage patients with comorbid conditions are explored, with an emphasis on the importance of a multidisciplinary approach to patient care. Online Access: http://www.cmeaccess.com/cme/ajm_fibro_program/

The Effect of Transdermal Nitroglycerine on Intrathecal Fentanyl with Bupivacaine for Postoperative Analgesia following Gynaecological Surgery

Fentanyl is a short-acting synthetic opioid with spinal analgesic properties and dose-dependent side-effects. The analgesic effect of opioids is mediated in part through activation of inhibitory descending pain pathways involving nitric oxide (as a central neurotransmitter) through the NO-cGMP system. This NO-cGMP pathway plays an important role in spinal nociception. The aim of the study was to evaluate the effect of transdermal nitroglycerine on the analgesic action of intrathecal fentanyl in patients undergoing abdominal hysterectomy. Patients (n=120) were randomised into one of four groups. All received 3 ml bupivacaine 0.5% plus 0.5 ml of an intrathecal test drug. Twenty minutes after lumbar puncture, a transdermal patch of either nitroglycerine or placebo was applied. Group B received spinal bupivacaine plus saline 0.5 ml and a placebo patch. Group B-N received bupivacaine plus saline 0.5 ml and a nitroglycerine patch. Group F received bupivacaine plus fentanyl 25 microg and a placebo patch. Group F-N received bupivacaine plus fentanyl 25 microg and a nitroglycerine patch. The duration of effective analgesia was longer in group FN (363.53 +/- 34.09 min) compared from the other groups (P < 0.001). The times to two-segment regression in group F-N and group F were 132.87 +/- 31.2 min and 126.40 +/- 26.81 min respectively. The visual analog scale pain score at the time of the first rescue analgesic was similar in all groups. We conclude that nitroglycerine does not result in postoperative analgesia but enhances the analgesic effect of intrathecal fentanyl.

Central Nervous System Abnormalities in Fibromyalgia and Chronic Fatigue Syndrome: New Concepts in Treatment

Fibromyalgia (FM) and chronic fatigue syndrome (CFS) are poorly understood disorders that share similar demographic and clinical characteristics. The etiology and pathophysiology of these diseases remain unclear. Because of the similarities between both disorders it was suggested that they share a common pathophysiological mechanisms, namely, central nervous system (CNS) dysfunction. Current hypotheses center on atypical sensory processing in the CNS and dysfunction of skeletal muscle nociception and the hypothalamic-pituitary-adrenal (HPA) axis. Researches suggest that the (CNS) is primarily involved in both disorders in regard to the pain, fatigue and sleep disturbances. Many patients experience difficulty with concentration and memory and many others have mood disturbance, including depression and anxiety. Although fibromyalgia is common and associated with substantial morbidity and disability, there are no US Food and Drug Administration (FDA)-approved treatments except pregabalin. Recent pharmacological treatment studies about fibromyalgia have focused on selective serotonin and norepinephrine (NE) reuptake inhibitors, which enhance serotonin and NE neurotransmission in the descending pain pathways and lack many of the adverse side effects associated with tricyclic medications. CFS is a descriptive term used to define a recognisable pattern of symptoms that cannot be attributed to any alternative condition. The symptoms are currently believed to be the result of disturbed brain function. To date, no pharmacological agent has been reliably shown to be effective treatment for CFS. Management strategies are therefore primarily directed at relief of symptoms and minimising impediments to recovery. This chapter presents data demonstrating CFS, abnormal pain processing and autonomic nervous system (ANS) dysfunction in FM and CFS and concludes by reviewing the new concepts in treatments in CFS and FM.

Acetaminophen Reinforces Descending Inhibitory Pain Pathways

The mechanism of the analgesic action of acetaminophen involves the serotonergic system. This study explores how acetaminophen interferes with serotonergic descending pain pathways. Eighteen rapid metabolizers of tropisetron were included in this double-blind cross-over study. After ethical approval, the healthy volunteers took 1 g oral acetaminophen (A) or placebo (p) combined with either the 5-HT3 antagonist tropisetron (T) (5 mg) or saline, intravenously, at weekly intervals. Mechanical pain thresholds, determined before and after a cold pressor test (CPT), were repeated seven times during the three post-dosing hours, and area under the concentration-time curves (AUCs) of the three treatments were compared. After CPT, AUC (%*min) of Ap (1,561+/-429) was larger than before CPT (393+/-382, P<0.05); these effects were totally inhibited by tropisetron. Acetaminophen reinforces descending inhibitory pain pathways; it suggests a supraspinal target for acetaminophen's antinociceptive action. This study also confirmed that there is a central serotonergic mechanism of action for acetaminophen that is not stimulus-dependent.

Anticipatory brainstem activity predicts neural processing of pain in humans

Previous neuroimaging studies have shown brain activity during not only the application of noxious stimuli, but also prior to stimulation. The functional significance of the anticipatory response, however, has yet to be explored. Two theoretical responses involve either a decrease or an increase in sensitivity of the nociceptive system. In a functional magnetic resonance imaging (fMRI) study, brainstem responses during anticipation and processing of thermal noxious stimuli were investigated. Twelve healthy subjects were warned prior to and then received noxious stimulation to their left hand. Behavioral data showed a positive correlation between the intensity of anticipation and pain. FMRI data revealed brainstem activation in the PAG during the anticipation period. When correlated with individual anticipation ratings, activation during anticipation included significant clusters within the entorhinal cortex and ventral tegmental area (VTA). During receipt, activation within the brainstem included the PAG, VTA, rostral ventromedial medulla (RVM), and the parabrachial nucleus (PB), all elements of descending pain pathways. Using a backward model approach, we explored the functional significance of the anticipatory neural response for subsequent pain processing. Results of this regression analysis revealed that insula activity during receipt was predicted by activity in both the entorhinal cortex and VTA during anticipation. We suggest that activation in both regions before and during pain may underlie anticipation and subsequent pain modulatory responses, possibly involving the appraisal and control of attention necessary for pain modulation. Together, the results suggest a possible role of brainstem areas in anticipatory mechanisms involved in the maintenance of chronic pain.

Rat/mouse hemokinin-1, a mammalian tachykinin peptide, markedly potentiates the antinociceptive effects of morphine administered at the peripheral and supraspinal level

Rat/mouse hemokinin 1 (r/m HK-1) is a mammalian tachykinin peptide whose biological functions are not fully understood. Our recent report showed that i.c.v. administration of r/m HK-1 could produce dose- and time-related antinociceptive effect at nanomole concentration, and naloxone significantly antagonized this effect. Thus, we provide indirect evidence favoring a role of NK 1 supraspinal receptors in the inhibitory control of descending pain pathways, a role that seems to partially involve the activation of the endogenous opioid systems. Based on this report, the present study was conducted to further investigate the direct functional interaction between supraspinal tachykinin (r/m HK-1) and opioid systems. The results demonstrate that i.c.v. administration of r/m HK-1 (5 nmol/kg) could significantly potentiate the antinociceptive effects of morphine which was injected at peripheral and supraspinal level. These antinociceptive effects were blocked by prior treatment with the classical opioid receptors antagonist naloxone, indicating that the potentiated analgesic response is mediated by opioid-responsive neurons. Consistent with previous biochemical data, a likely mechanism underlying the peptide-mediated enhancement of opioid analgesia may center on the ability of r/m HK-1 to release endogenous opioid peptides. We suggest that there may be a cascade amplification mechanism in pain modulation when the two agents were co-administrated. The synergistic analgesic relationship of morphine and r/m HK-1 established here supports the hypothesis that supraspinal tachykinin and peripheral and central opioid systems have a direct functional interaction in the modulation of local nociceptive responses.

Biology and therapy of fibromyalgia. New therapies in fibromyalgia

Fibromyalgia is a chronic, musculoskeletal pain condition that predominately affects women. Although fibromyalgia is common and associated with substantial morbidity and disability, there are no US Food and Drug Administration-approved treatments. However, progress has been made in identifying pharmacological and non-pharmacological treatments for fibromyalgia. Recent pharmacological treatment studies have focused on selective serotonin and norepinephrine reuptake inhibitors, which enhance serotonin and norepinephrine neurotransmission in the descending pain pathways and lack many of the adverse side effects associated with tricyclic medications. Promising results have also been reported for medications that bind to the α2δ subunit of voltage-gated calcium channels, resulting in decreased calcium influx at nerve terminals and subsequent reduction in the release of several neurotransmitters thought to play a role in pain processing. There is also evidence to support exercise, cognitive behavioral therapy, education, and social support in the management of fibromyalgia. It is likely that many patients would benefit from combinations of pharmacological and non-pharmacological treatments, but more study is needed.

Duloxetine vs. placebo in patients with painful diabetic neuropathy

The aim of this study was to examine the efficacy and safety of duloxetine, a balanced and potent dual reuptake inhibitor of serotonin and norepinephrine, in the management of diabetic peripheral neuropathic pain. Serotonin and norepinephrine are thought to inhibit pain via descending pain pathways. In a 12-week, multicenter, double-blind study, 457 patients experiencing pain due to polyneuropathy caused by Type 1 or Type 2 diabetes mellitus were randomly assigned to treatment with duloxetine 20 mg/d (20 mg QD), 60 mg/d (60 mg QD), 120 mg/d (60 mg BID), or placebo. The diagnosis was confirmed by a score of at least 3 on the Michigan Neuropathy Screening Instrument. The primary efficacy measure was the weekly mean score of the 24-h Average Pain Score, which was rated on an 11-point (0–10) Likert scale (no pain to worst possible pain) and computed from diary scores between two site visits. Duloxetine 60 and 120 mg/d demonstrated statistically significant greater improvement compared with placebo on the 24-h Average Pain Score, beginning 1 week after randomization and continuing through the 12-week trial. Duloxetine also separated from placebo on nearly all the secondary measures including health-related outcome measures. Significantly more patients in all three active-treatment groups achieved a 50% reduction in the 24-h Average Pain Score compared with placebo. Duloxetine treatment was considered to be safe and well tolerated with less than 20 percent discontinuation due to adverse events. Duloxetine at 60 and 120 mg/d was safe and effective in the management of diabetic peripheral neuropathic pain.

The use of opioids in the postoperative setting: Focus on morphine, hydromorphone, and fentanyl

U P 7 OPIOID ANALGESICS are crucial for providing pain control during and after surgery. Opioids provide analgesia by binding to specific receptors located primarily in the brain and spinal cord to inhibit the release of substance P. This, in effect, blocks the pain pathways ascending to the brain, where pain is perceived. Opioids also activate descending pain pathways to inhibit the transmission of nociceptive information.

The importance of animal research to nursing science

Two of the 79 Presidential Early Career Award for Scientists and Engineers (PECASE) recipients have been nurses, and both employ animal models in their research. The PECASE is the highest honor awarded by the U.S. government to young professionals in the beginning of their research career. Janean Holden, a 1999 recipient, was recognized for her study to map descending pain pathways from the hypothalamus to identify points at which medications or non-pharmacologic interventions might act upon pain transmissions. Pain is acknowledged as a high cost symptom in terms of both human and financial burden, and symptom management is a primary focus of care. Leslie Ritter received the PECASE in 2000 for her study that investigated the locations, mechanisms and clinical significance of platelet and white blood cell accumulation in the brain following stroke. As understanding of these inflammatory sequelae of stroke increases, interventions to diminish their role in brain injury can be developed to reduce functional impairment following stroke. Improving functional status is a primary focus of care. Such national recognition of research supported by the National Institute for Nursing Research (NINR) is a tribute to our contributions to the care of human health. Gayle Giboney Page is an Associate Professor and holds the Independence Foundation Chair in Nursing Education at Johns Hopkins University School of Nursing, Baltimore, MD.

The Role of Duloxetine in the Treatment of Depression and Associated Painful Physical Symptoms.

The Role of Duloxetine in the Treatment of Depression and Associated Painful Physical Symptoms.

Physiology of acute pain in preterm infants

Abstract Understanding the pain physiology of the preterm infant is essential to the provision of effective pain prevention and pain management. Peripheral and ascending pain pathways are mature by 20 weeks of gestation so infants are completely capable of feeling pain. The expression of pain in preterm infants is well documented. However, the immature descending pain pathway and lack of serotonin until 6 to 8 weeks after birth along with a greater density of pain receptors in the skin mean that preterm infants experience more severe pain than adults. The duration of the pain is longer, and the consequences of repeated painful procedures create permanent structural changes in the vulnerable nervous system of the preterm infant. Prevention of pain may preclude the permanent structural changes in the preterm nervous system, and adequate management when pain is necessary may prevent the psychologic and emotional consequences of repeated pain in the preterm infant. Copyright © 2001 by W.B. Saunders Company

Modulation of carbachol-induced antinociception from the rat periaqueductal gray

The tail-flick latency (TFL) and the vocalisation test (VT) thresholds were all increased by microinjecting CCh into the dorsal periaqueductal gray (dPAG) of rats. The effects on the TFL were mimicked by dimethyl-phenylpiperazinium, and inhibited by local mecamylamine or intraperitoneal (i.p.) phenoxybenzamine. The effects on the VT were mimicked by bethanechol and inhibited by local mecamylamine, atropine or naloxone. The effects on the thresholds for motor defence reaction were inhibited by i.p. methysergide or naloxone, and prolonged by i.p. phenoxybenzamine. The effects on the threshold for vocalisation during the stimulation were blocked by i.p. methysergide and shortened by i.p. phenoxybenzamine or naloxone. No significant effect of CCh was found on open arm exploration of rats in the elevated plus maze paradigm. We conclude that the effects of CCh from the dPAG is not due to an anxiolytic effect, and depends on the activation of local cholinergic and opioid sites for the supraspinal modulation of “affective” component of pain response, and nicotinic sites for the activation of descending pain pathways.

Antihyperalgesic effects of delta opioid agonists in a rat model of chronic inflammation.

Opioid receptors in the brain activate descending pain pathways to inhibit the nociceptive response to acute noxious stimuli. The aim of the present study was to clarify the role of supraspinal opioid receptors in modulating the nociceptive response to persistent inflammation in rats. Subcutaneous administration of 50 microl of complete Freund's Adjuvant (CFA) into the plantar surface of the hindpaw induced a significant decrease in paw withdrawal latency to thermal stimuli (P<0.01) at 24 h post-injection. Intracerebroventricular (i.c.v.) administration of the mu opioid receptor agonists, DAMGO and morphine, and the delta opioid receptor agonists, deltorphin II and SNC80, significantly reversed the hyperalgesic response associated with peripheral inflammation in a dose-dependent manner (P<0.0001). The mu and delta agonists also significantly attenuated the antinociceptive response to acute thermal stimulation in rats (P<0.001). However, deltorphin II and SNC80 were less potent, and in the case of SNC80 less efficacious, in modulating the response to acute thermal nociception in comparison to hyperalgesia associated with persistent inflammation. These results indicate that mu and delta opioid receptors in the brain modulate descending pain pathways to attenuate the nociceptive response to acute thermal stimuli in both normal and inflamed tissues. The heightened response to delta agonists in the hyperalgesia model suggests that delta opioid receptors in the brain are promising targets for the treatment of pain arising from chronic inflammation.