Bethany Remeniuk

Afferent Drive Elicits Ongoing Pain in a Model of Advanced Osteoarthritis

Summary Monosodium iodoacetate (MIA)‐induced ongoing pain depends on input from the joint; blockade of TRPV1 and TRPA1 channels fails to block MIA‐induced ongoing pain. Abstract Osteoarthritis (OA) is a chronic condition characterized by pain during joint movement. Additionally, patients with advanced disease experience pain at rest (ie, ongoing pain) that is generally resistant to nonsteroidal antiinflammatory drugs. Injection of monosodium iodoacetate (MIA) into the intraarticular space of the rodent knee is a well‐established model of OA that elicits weight‐bearing asymmetry and referred tactile and thermal hypersensitivity. Whether ongoing pain is present in this model is unknown. Additionally, the possible relationship of ongoing pain to MIA dose is not known. MIA produced weight asymmetry, joint osteolysis, and cartilage erosion across a range of doses (1, 3, and 4.8 mg). However, only rats treated with the highest dose of MIA showed conditioned place preference to a context paired with intraarticular lidocaine, indicating relief from ongoing pain. Diclofenac blocked the MIA‐induced weight asymmetry but failed to block MIA‐induced ongoing pain. Systemic AMG9810, a transient receptor potential V1 channel (TRPV1) antagonist, effectively blocked thermal hypersensitivity, but failed to block high‐dose MIA‐induced weight asymmetry or ongoing pain. Additionally, systemic or intraarticular HC030031, a TRPA1 antagonist, failed to block high‐dose MIA‐induced weight asymmetry or ongoing pain. Our studies suggest that a high dose of intraarticular MIA induces ongoing pain originating from the site of injury that is dependent on afferent fiber activity but apparently independent of TRPV1 or TRPA1 activation. Identification of mechanisms driving ongoing pain may enable development of improved treatments for patients with severe OA pain and diminish the need for joint replacement surgery.

Behavioral and neurochemical analysis of ongoing bone cancer pain in rats.

Abstract Cancer-induced bone pain is described as dull, aching ongoing pain. Ongoing bone cancer pain was characterized after intratibial injection of breast cancer cells in rats. Cancer produced time-dependent bone remodeling and tactile hypersensitivity but no spontaneous flinching. Conditioned place preference (CPP) and enhanced dopamine (DA) release in the nucleus accumbens (NAc) shell was observed after peripheral nerve block (PNB) selectively in tumor-bearing rats revealing nociceptive-driven ongoing pain. Oral diclofenac reversed tumor-induced tactile hypersensitivity but did not block PNB-induced CPP or NAc DA release. Tumor-induced tactile hypersensitivity, and PNB-induced CPP and NAc DA release, was blocked by prior subcutaneous implantation of a morphine pellet. In sham rats, morphine produced a modest but sustained increase in NAc DA release. In contrast, morphine produced a transient 5-fold higher NAc DA release in tumor bearing rats compared with sham morphine rats. The possibility that this increased NAc DA release reflected the reward of pain relief was tested by irreversible blockade of rostral anterior cingulate cortex (rACC) &mgr;-opioid receptors (MORs). The rACC MOR blockade prevented the morphine-induced transient increased NAc DA release in tumor bearing rats but did not affect morphine-induced effects in sham-operated animals. Consistent with clinical experience, ongoing cancer pain was controlled by morphine but not by a dose of diclofenac that reversed evoked hypersensitivity. Additionally, the intrinsic reward of morphine can be dissociated from the reward of relief of cancer pain by blockade of rACC MOR. This approach allows mechanistic and therapeutic assessment of ongoing cancer pain with likely translation relevance.

Altered brain structure and function associated with sensory and affective components of classic trigeminal neuralgia.

Abstract Classic trigeminal neuralgia (CTN) is a chronic neuropathic pain state characterized by intense, piercing spasms of the orofacial region, and may be attributable to abnormal pain processing in the central nervous system. Our study investigated neuronal alterations using voxel-based morphometry (VBM), diffuse tensor imaging (DTI), and resting-state functional connectivity in 38 patients with CTN and 38 matched healthy controls. For voxel-based morphometry analyses, patients with CTN displayed gray matter volume (GMV) reductions in the anterior-cingulate cortex (ACC) and mid-cingulate cortex, insula, secondary somatosensory cortex (S2), primary motor cortex (M1), premotor area, and several regions in the temporal lobe. For DTI analysis, patients compared with controls had increased mean diffusivity (MD) and decreased fractional anisotropy (FA) in the corpus callosum and the bilateral corona radiata, and increased mean diffusivity with no fractional anisotropy changes across the bilateral superior longitudinal fasciculus, the internal and external capsule, the thalamus and brainstem. Additionally, patients with CTN had enhanced functional connectivity between the right insula/S2 and ACC, medial prefrontal cortex, posterior cingulate cortex, and bilateral dorsolateral prefrontal cortex. Furthermore, gray matter volume of left inferior temporal gyrus negatively correlated with current pain intensity and disease duration in patients, and connectivity of the right insula/S2-ACC was negatively correlated with pain intensity, depression, and anxiety ratings. This study provides multiple lines of evidence supporting aberrant structural and functional patterns that are observed in patients with CTN, which may help us better understand the pathophysiology of CTN and facilitate the development of new therapies for this disease.

Kappa opioid receptor antagonists: A possible new class of therapeutics for migraine prevention:

Background Stress is the most commonly reported migraine trigger. Dynorphin, an endogenous opioid peptide acting preferentially at kappa opioid receptors (KORs), is a key mediator of stress responses. The aim of this study was to use an injury-free rat model of functional cephalic pain with features of migraine and medication overuse headache (MOH) to test the possible preventive benefit of KOR blockade on stress-induced cephalic pain. Methods Following sumatriptan priming to model MOH, rats were hyper-responsive to environmental stress, demonstrating delayed cephalic and extracephalic allodynia and increased levels of CGRP in the jugular blood, consistent with commonly observed clinical outcomes during migraine. Nor-binaltorphimine (nor-BNI), a long-acting KOR antagonist or CYM51317, a novel short-acting KOR antagonist, were given systemically either during sumatriptan priming or immediately before environmental stress challenge. The effects of KOR blockade in the amygdala on stress-induced allodynia was determined by administration of nor-BNI into the right or left central nucleus of the amygdala (CeA). Results KOR blockade prevented both stress-induced allodynia and increased plasma CGRP. Stress increased dynorphin content and phosphorylated KOR in both the left and right CeA in sumatriptan-primed rats. However, KOR blockade only in the right CeA prevented stress-induced cephalic allodynia as well as extracephalic allodynia, measured in either the right or left hindpaws. U69,593, a KOR agonist, given into the right, but not the left, CeA, produced allodynia selectively in sumatriptan-primed rats. Both stress and U69,593-induced allodynia were prevented by right CeA U0126, a mitogen-activated protein kinase inhibitor, presumably acting downstream of KOR. Conclusions Our data reveal a novel lateralized KOR circuit that mediated stress-induced cutaneous allodynia and increased plasma CGRP in an injury-free model of functional cephalic pain with features of migraine and medication overuse headache. Selective, small molecule, orally available, and reversible KOR antagonists are currently in development and may represent a novel class of preventive therapeutics for migraine.

Prevention of stress- or nitric oxide donor-induced medication overuse headache by a calcitonin gene-related peptide antibody in rodents.

Objective The objective of this study was the determination of the role of calcitonin gene-related peptide (CGRP) in the induction of medication overuse headache (MOH)-related migraine in an injury-free preclinical model. Methods Rats were primed by a 7-day period of exposure to acute migraine therapies including sumatriptan and morphine. After an additional 14-day drug-free period, rats were exposed to putative migraine triggers including bright light stress (BLS) or nitric oxide (NO) donor in the presence or absence of TEV48125, a fully humanized CGRP antibody. Cutaneous allodynia (CA) was used as an outcome measure and CGRP blood and cerebrospinal fluid (CSF) levels were measured. Results BLS and NO donor challenge evoked delayed, long-lasting CA selectively in rats that were previously treated with sumatriptan or morphine. BLS produced a significant increase in CGRP in the plasma, but not CSF, in animals that were previously exposed to sumatriptan compared to saline controls. TEV48125 did not modify baseline tactile thresholds or produce behavioral side effects, but significantly inhibited both BLS- and NO donor-induced CA in animals that were previously primed with sumatriptan or morphine; an isotype control protein that does not bind CGRP had no effect. Interpretation These data suggest that acute migraine medications may promote MOH in susceptible individuals through CGRP-dependent mechanisms and that anti-CGRP antibodies may be a useful clinical strategy for the treatment of MOH.

Hedonic and motivational responses to food reward are unchanged in rats with neuropathic pain.

Abstract Rewards influence responses to acute painful stimuli, but the relationship of chronic pain to hedonic or motivational aspects of reward is not well understood. We independently evaluated hedonic qualities of sweet or bitter tastants and motivation to seek food reward in rats with experimental neuropathic pain induced by L5/6 spinal nerve ligation. Hedonic response was measured by implantation of intraoral catheters to allow passive delivery of liquid solutions, and “liking/disliking” responses were scored according to a facial reactivity scale. Spinal nerve ligation rats did not differ from controls in either “liking” or “disliking” reactions to intraoral sucrose or quinine, respectively, at postsurgery day 21, suggesting no differences in perceived hedonic value of sweet or bitter tastants. To assess possible motivational deficits during acute and chronic pain, we used fixed- and progressive-ratio response paradigms of sucrose pellet presentation in rats with transient inflammatory or chronic neuropathic pain. Assessment of response acquisition and break points under the progressive ratio schedule revealed no differences between sham and spinal nerve ligation rats for up to 120 days after injury. However, rats with inflammation showed decrements in lever pressing and break points on days 1 and 2 after complete Freund adjuvant injection that normalized by day 4, consistent with transient ongoing pain. Thus, although acute ongoing inflammatory pain may transiently reduce reward motivation, we did not detect influences of chronic neuropathic pain on hedonic or motivational responses to food rewards. Adaptations that allow normal reward responding to food regardless of chronic pain may be of evolutionary benefit to promote survival.

Partial sleep deprivation attenuates the positive affective system: Effects across multiple measurement modalities

Objective Ample behavioral and neurobiological evidence links sleep and affective functioning. Recent self-report evidence suggests that the affective problems associated with sleep loss may be stronger for positive versus negative affective state and that those effects may be mediated by changes in electroencepholographically measured slow wave sleep (SWS). In the present study, we extend those preliminary findings using multiple measures of affective functioning. Design In a within-subject randomized crossover experiment, we tested the effects of one night of sleep continuity disruption via forced awakenings (FA) compared to one night of uninterrupted sleep (US) on three measures of positive and negative affective functioning: self-reported affective state, affective pain modulation, and affect-biased attention. Setting The study was set in an inpatient clinical research suite. Participants Healthy, good sleeping adults (N = 45) were included. Measurement and Results Results indicated that a single night of sleep continuity disruption attenuated positive affective state via FA-induced reductions in SWS. Additionally, sleep continuity disruption attenuated the inhibition of pain by positive affect as well as attention bias to positive affective stimuli. Negative affective state, negative affective pain facilitation, nor negative attention bias were altered by sleep continuity disruption. Conclusions The present findings, observed across multiple measures of affective function, suggest that sleep continuity disruption has a stronger influence on the positive affective system relative to the negative affective affective system.

Mediation of Movement-Induced Breakthrough Cancer Pain by IB4-Binding Nociceptors in Rats

Cancer-induced bone pain is characterized by moderate to severe ongoing pain that commonly requires the use of opiates. Even when ongoing pain is well controlled, patients can suffer breakthrough pain (BTP), episodic severe pain that “breaks through” the medication. We developed a novel model of cancer-induced BTP using female rats with mammary adenocarcinoma cells sealed within the tibia. We demonstrated previously that rats with bone cancer learn to prefer a context paired with saphenous nerve block to elicit pain relief (i.e., conditioned place preference, CPP), revealing the presence of ongoing pain. Treatment with systemic morphine abolished CPP to saphenous nerve block, demonstrating control of ongoing pain. Here, we show that pairing BTP induced by experimenter-induced movement of the tumor-bearing hindlimb with a context produces conditioned place avoidance (CPA) in rats treated with morphine to control ongoing pain, consistent with clinical observation of BTP. Preventing movement-induced afferent input by saphenous nerve block before, but not after, hindlimb movement blocked movement-induced BTP. Ablation of isolectin B4 (IB4)-binding, but not TRPV1+, sensory afferents eliminated movement-induced BTP, suggesting that input from IB4-binding fibers mediates BTP. Identification of potential molecular targets specific to this population of fibers may allow for the development of peripherally restricted analgesics that control BTP and improve quality of life in patients with skeletal metastases. SIGNIFICANCE STATEMENT We present a novel preclinical measure of movement-induced breakthrough pain (BTP) that is observed in the presence of morphine controlling ongoing pain. Blockade of sensory input before movement prevented BTP, whereas nerve block after movement failed to reverse BTP. These observations indicate that blocking peripheral sensory input may prevent BTP and targeting central sites may be required for pain relief once BTP has been initiated. Preventing sensory input from TRPV1-expressing fibers failed to alter movement-induced BTP. In contrast, preventing sensory input from isolectin B4 (IB4)-binding fibers blocked movement-induced BTP. Therefore, examining molecular targets on this population of nociceptive fibers may prove useful for developing an improved strategy for preventing BTP in cancer patients with skeletal metastases.

Disease modifying actions of IL-6 blockade in a rat model of bone cancer pain

Abstract Metastasis of cancer to the skeleton represents a debilitating turning point in the lives of patients. Skeletal metastasis leads to moderate to severe ongoing pain along with bone remodeling that can result in fracture, events that dramatically diminish quality of life. Interleukin-6 (IL-6) levels are elevated in patients with metastatic breast cancer and are associated with a lower survival rate. We therefore determined the consequences of inhibition of IL-6 signaling using a novel small molecule antagonist, TB-2-081, on bone integrity, tumor progression, and pain in a rodent model of breast cancer. Rat MAT B III mammary adenocarcinoma cells were injected and sealed within the tibia of female Fischer rats. Growth of these cells within the rat tibia elicited increased IL-6 levels both within the bone exudate and in the plasma, produced ongoing pain and evoked hypersensitivity, and bone fracture that was observed by approximately day 12. Systemic TB-2-081 delivered by subcutaneous osmotic minipumps starting at tumor implantation prevented tumor-induced ongoing bone pain and evoked hypersensitivity without altering tumor growth. Remarkably, TB-2-081 infusion significantly reduced osteolytic and osteoblastic bone remodeling and time to fracture likely by decreasing osteoclastogenesis and associated increase in bone resorption. These findings indicate that blockade of IL-6 signaling may represent a viable, disease-modifying strategy to prevent tumor-induced bone remodeling allowing for stabilization of bone and decreased fractures as well as diminished ongoing pain that may improve quality of life of patients with skeletal metastases. Notably, anti-IL-6 antibodies are clinically available allowing for rapid testing of these possibilities in humans.

Is the brain reward system a mechanism of the association of sleep and pain

Department of Psychiatry & Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA *Author for correspondence: Tel.: +1 410 550 7901; pfinan1@jhu.edu