Neurotransmitter systems involved in placebo and nocebo effects in healthy participants and patients with chronic pain: a systematic review.

The investigation of neurotransmitter systems in placebo and nocebo effects has improved our understanding of these phenomena. Yet, most studies involve healthy participants. Because the pain modulatory system may differ in healthy participants and patients with chronic pain, it is important to investigate the evidence for neurotransmitter involvement in placebo and nocebo effects in each of these populations. PubMed, Embase, and Scopus databases, and the Cochrane Library were searched for articles investigating the endogenous opioid, endocannabinoid, dopaminergic, oxytocinergic, vasopressinergic, and cholecystokininergic (CCKergic) systems in placebo and nocebo effects in pain. Twenty-eight placebo and 2 nocebo studies were included. Vote counting was used to balance the number of positive vs negative findings. In healthy participants, the endogenous opioid, endocannabinoid, and vasopressinergic systems were involved in placebo effects, whereas findings on the dopaminergic and oxytocinergic systems were mixed. In patients with chronic pain, only 4 studies investigated neurotransmitters showing no involvement of the endogenous opioid system and mixed findings regarding the dopaminergic system. As to nocebo effects, 2 studies suggest that the CCKergic system is involved in nocebo effects in healthy participants. Overall, research has come a long way in specifying the neurotransmitter systems involved in placebo effects in healthy participants. Yet, evidence for the involvement of neurotransmitter systems in placebo effects in patients with chronic pain and in nocebo effects in healthy participants and patients is scarce. Based on the existing evidence, this systematic review suggests that knowledge obtained in healthy participants may not necessarily be transferred to chronic pain.

Coexisting mechanical hypersensitivity and anxiety in a rat model of spinal cord injury and the effect of pregabalin, morphine, and midazolam treatment.

Background and purpose Spinal cord injury (SCI) has detrimental consequences that include chronic neuropathic pain, which is seen in 40-50% of patients, and symptoms of anxiety and depression, which affect 13-45% of SCI patients. The coexistence of pain, anxiety, and depression is known from other neuropathic pain conditions, but the relationship between these symptoms is not clear and has not been investigated in a preclinical model of SCI so far. The aim of this study was to investigate anxiety-like behavior and at-level mechanical hypersensitivity following experimental spinal cord contusion (SCC) in female Sprague-Dawley rats, and the effects of analgesic and anxiolytic drugs. Methods Mechanical sensitivity and elevated plus maze (EPM) behavior were measured pre- and postinjury in SCC and sham animals. Pregabalin 30 mg/kg, morphine 3 mg/kg, midazolam 0.5 mg/kg, and 0.9% NaCl were evaluated in a randomly allocated, blinded balanced design. Results SCC animals developed persistent at-level mechanical hypersensitivity and decreased open arm activity in the EPM, which indicates an anxiety-like state. Pregabalin, a dual-acting analgesic and anxiolytic drug reduced both hypersensitivity and anxiety-like behavior, while the analgesic drug morphine only reduced hypersensitivity. The anxiolytic drug midazolam in the dose used had no effect on either parameter. Conclusions SCC animals developed long lasting coexisting at-level mechanical hypersensitivity and anxiety-like behavior, but there was no evidence to support a causal relationship between pain and anxiety following SCI. Implications The findings that at-level mechanical hypersensitivity and anxiety-like behavior develops concomitantly in the spinal cord contusion models and that both symptoms is persistent provide basis for further investigation of the mechanisms and connection behind these two clinically relevant symptoms after injury to the central nervous system.

Dopaminergic tone does not influence pain levels during placebo interventions in patients with chronic neuropathic pain.

Placebo effects have been reported in patients with chronic neuropathic pain. Expected pain levels and positive emotions are involved in the observed pain relief, but the underlying neurobiology is largely unknown. Patients with neuropathic pain are highly motivated for pain relief, and as motivational factors such as expectations of reward, as well as pain processing in itself, are related to the dopaminergic system, it can be speculated that dopamine release contributes to placebo effects in neuropathic pain. Nineteen patients with neuropathic pain after thoracic surgery were tested during a placebo intervention consisting of open and hidden applications of the pain-relieving agent lidocaine (2 mL) and no treatment. The dopamine antagonist haloperidol (2 mg) and the agonist levodopa/carbidopa (100/25 mg) were administered to test the involvement of dopamine. Expected pain levels, desire for pain relief, and ongoing and evoked pain were assessed on mechanical visual analog scales (0-10). Significant placebo effects on ongoing (P ≤ 0.003) and evoked (P ≤ 0.002) pain were observed. Expectancy and desire accounted for up to 41.2% and 71.5% of the variance in ongoing and evoked pain, respectively, after the open application of lidocaine. We found no evidence for an effect of haloperidol and levodopa/carbidopa on neuropathic pain levels (P = 0.071-0.963). Dopamine seemed to influence the levels of expectancy and desire, yet there was no evidence for indirect or interaction effects on the placebo effect. This is the first study to suggest that dopamine does not contribute to placebo effects in chronic neuropathic pain.

Spinal cord injury pain: mechanisms and management.

Patients with spinal cord injury (SCI) may experience several types of chronic pain, including peripheral and central neuropathic pain, pain secondary to overuse, painful muscle spasms, and visceral pain. An accurate classification of the patient's pain is important for choosing the optimal treatment strategy. In particular, neuropathic pain appears to be persistent despite various treatment attempts. In recent years, we have gained increasing knowledge of SCI pain mechanisms from experimental models and clinical studies. Nevertheless, treatment remains difficult and inadequate. In line with the recommendations for peripheral neuropathic pain, evidence from randomized controlled treatment trials suggests that tricyclic antidepressants and pregabalin are first-line treatments. This review highlights the diagnosis and classification of SCI pain and recent improvements in the understanding of underlying mechanisms, and provides an update on treatment of SCI pain.

Pain in spinal cord injury.

SUMMARY An important and detrimental effect of spinal cord injury (SCI) is pain, which develops in approximately two-thirds of all SCI patients, while approximately half of SCI patients develop chronic neuropathic pain (NP). Thus far, there is no cure for SCI NP, and oral pharmacological intervention is often inadequate, commonly resulting in a pain reduction of only 20-30%. In this short review, we will present an overview of the important features of SCI pain including taxonomy, epidemiology and classification, as well as a suggested oral pharmacological treatment strategy for SCI NP and the current evidence available from randomized placebo-controlled trials. Considerations and evidence for the nonpharmacological treatment of SCI will be discussed briefly.

Pregabalin attenuates place escape/avoidance behavior in a rat model of spinal cord injury.

Spinal cord injury (SCI) pain in humans is difficult to treat, and the lack of valid methods to measure behavior comparable to the complex human pain experience preclinically represents an important obstacle to finding better treatments for this type of central pain. The place escape/avoidance paradigm (PEAP) relies on the active choice of an animal between its natural preference for a dark environment or pain relief, and it has been suggested to measure the affective-motivational component of pain. We have modified the method to a T10 spinal cord contusion model (SCC) of at-level central neuropathic pain in Sprague-Dawley rats. In order to demonstrate sensitivity to change in escape/avoidance behavior and thus the applicability of the PEAP method to predict drug efficacy, we investigated the effect of pregabalin (30 mg/kg) treatment in a randomized design. SCC animals displayed increased escape/avoidance behavior postinjury, indicating at-level mechanical hypersensitivity. Second, we found no correlation between state anxiety levels in SCC animals (elevated plus maze) and PEAP behavior, suggesting that the PEAP measurement is not biased by differences in anxiety levels. Third, we demonstrated a decrease in escape/avoidance behavior in response to treatment with the analgesic drug pregabalin. Thus, the PEAP may be applicable as a surrogate correlate of human pain. In conclusion, the primary finding in this study was a sensitivity to change in escape/avoidance behavior induced by pharmacological modulation with analgesics, supporting the use of the PEAP as a central outcome measure in preclinical SCI pain research.

Spinal-, brainstem- and cerebrally mediated responses at- and below-level of a spinal cord contusion in rats: evaluation of pain-like behavior.

Pain is a frequent consequence of spinal cord injury (SCI) which may profoundly impair the patients' quality of life. Valid experimental models and methods are therefore desirable in the search for better treatments. Usually, experimental pain assays depend on stimulus-evoked withdrawal responses; however, this spinal-mediated reflex response may be particularly problematic when evaluating below-level SCI pain due to the development of hyperactive reflex circuitries. In this study, we applied and compared assays measuring cold (acetone), static (von Frey filaments), and dynamic mechanical (soft brush) hypersensitivity at different levels of the neuroaxis at and below the level of injury in a rat model of SCI. We induced an experimental SCI (MASCIS 25 mm weight-drop) and evaluated the development of spinal reflexes (withdrawal), spinal-brainstem-spinal reflexes (licking, guarding, struggling, vocalizing, jumping, and biting) and cerebral-dependent behavior (place escape/avoidance paradigm (PEAP)). We demonstrated increased brainstem reflexes and cerebrally mediated aversive reactions to stimuli applied at the level of SCI, suggesting development of at-level evoked pain behavior. Furthermore, stimulation below-level increased innate reflex responses without increasing brainstem reflexes or aversive behavior in the PEAP, suggesting development of the spasticity syndrome rather than pain-like behavior. While spinal reflex measures are acceptable for studying changes in the spinal reflex pathways and spinal cord, they are not suited as nociceptive behavioral measures. Measuring brainstem organized responses eliminates the bias associated with the spastic syndrome, but pain requires cortical involvement. Methods depending on cortical structures, as the PEAP, are therefore optimal endpoints in animal models of central pain.

Pharmacological management of neuropathic pain following spinal cord injury.

Spinal cord injury (SCI) has a number of severe and disabling consequences, including chronic pain, and around 40% of patients develop persistent neuropathic pain. Pain following SCI has a detrimental impact on the patient's quality of life and is a major specific healthcare problem in its own right. Thus far, there is no cure for the pain and oral pharmaceutical intervention is often inadequate, commonly resulting in a reduction of only 20-30% in pain intensity. Neuropathic pain sensations are characterized by spontaneous persistent pain and a range of abnormally evoked responses, e.g. allodynia (pain evoked by normally non-noxious stimuli) and hyperalgesia (an increased response to noxious stimuli). Neuropathic pain following SCI may be present at or below the level of injury. Oral pharmacological agents used in the treatment of neuropathic pain act either by depressing neuronal activity, by blocking sodium channels or inhibiting calcium channels, by increasing inhibition via GABA agonists, by serotonergic and noradrenergic reuptake inhibition, or by decreasing activation via glutamate receptor inhibition, especially by blocking the NMDA receptor. At present, only ten randomized, double-blind, controlled trials have been performed on oral drug treatment of pain after SCI, the results of most of which were negative. The studies included antidepressants (amitriptyline and trazodone), antiepileptics (gabapentin, pregabalin, lamotrigine and valproate) and mexiletine. Gabapentin, pregabalin and amitriptyline showed a significant reduction in neuropathic pain following SCI. Cannabinoids have been found to relieve other types of central pain, and serotonin noradrenaline reuptake inhibitors as well as opioids relieve peripheral neuropathic pain and may be used to treat patients with SCI pain.

Differential effects of mGluR1 and mGlur5 antagonism on spatial learning in rats.

The effects of selective mGluR1 and mGluR5 antagonists on long-term acquisition were tested in a spatial three-choice reward-finding test. Bilateral prelimbic injections of the mGluR1 antagonist, (S)-4-carboxyphenylglycine (4-CPG), before training sessions blocked acquisition of correct performance between sessions. Similar injections given after full training of a control group significantly impaired correct performance without causing a complete block. Pretraining injections (intraperitoneal or intravenous) of the systemically active mGluR5 antagonist, 2-methyl-6-(phenylethynyl)pyridine (MPEP), had no effect on long-term acquisition in the reward-finding task. In an open-field test, bilateral prelimbic pretest application of 4-CPG prevented normal adaptation of spontaneous exploration as seen in control animals. MPEP, on the other hand, had no effect. In conclusion, the results confirmed that mGluR1 is involved in spatial long-term acquisition and suggested an additional role in recall of acquired skills. Furthermore, it was concluded that antagonism of mGluR1 or mGluR5 had different effects both in the appetitive spatial task and in the open-field test.