Jessica A. Boyette-Davis

Intraepidermal nerve fiber loss corresponds to the development of taxol-induced hyperalgesia and can be prevented by treatment with minocycline.

&NA; Loss of intraepidermal nerve fibers (IENFs) has been speculated to play a critical role in the development of various neuropathies. In this study, the density of IENFs were studied over time during the induction of Taxol (Bristol‐Myers Squibb, NY, USA)‐induced chemoneuropathy and compared with the changes in IENFs in animals co‐treated with Taxol plus the protective agent minocycline. Rats were injected (intraperitoneally) with 2 mg/kg of Taxol every other day for four injections (day 1, 3, 5, and 7). Minocycline (25 mg/kg) was given in a separate group of rats 24 h prior to the first dose of Taxol and every day for the next 9 days (day 0 through 9). Animals were tested for mechanical paw withdrawal thresholds prior to any drug administrations and again on day 7, 14, and 30. Immunohistochemistry using the pan‐neuronal marker protein gene product 9.5 was performed on glabrous skin of the hind‐paw foot pad to stain for IENFs also on day 7, 14, and 30. The results show that Taxol‐treated animals developed mechanical sensitivity and corresponding IENF loss. Animals receiving minocycline plus Taxol showed no hyperalgesia or loss of IENFs. This study confirms, for the first time, that a loss of IENFs occurs as a neuropathy develops, and further shows a protection against both IENF loss and hyperalgesia with minocycline treatment. The progression of Taxol‐induced mechanical hypersensitivity coincides with loss of intraepidermal nerve fibers, and the hyperalgesia and nerve fiber loss were prevented with minocycline treatment.

Induction of Monocyte Chemoattractant Protein-1 (MCP-1) and Its Receptor CCR2 in Primary Sensory Neurons Contributes to Paclitaxel-Induced Peripheral Neuropathy

UNLABELLED The use of paclitaxel (Taxol), a microtubule stabilizer, for cancer treatment is often limited by its associated peripheral neuropathy (chemotherapy-induced peripheral neuropathy [CIPN]), which predominantly results in sensory dysfunction, including chronic pain. Here we show that paclitaxel CIPN was associated with induction of chemokine monocyte chemoattractant protein-1 (MCP-1) and its cognate receptor CCR2 in primary sensory neurons of dorsal root ganglia. Immunostaining revealed that MCP-1 was mainly expressed in small nociceptive neurons whereas CCR2 was expressed in large and medium-sized myelinated neurons. Direct application of MCP-1 consistently induced intracellular calcium increases in dorsal root ganglia large and medium-sized neurons but not in small neurons mainly dissociated from paclitaxel-treated but not vehicle-treated animals. Paclitaxel also induced increased expression of MCP-1 in spinal astrocytes, but no CCR2 signal was detected in the spinal cord. Local blockade of MCP-1/CCR2 signaling by anti-MCP-1 antibody or CCR2 antisense oligodeoxynucleotides significantly attenuated paclitaxel CIPN phenotypes including mechanical hypersensitivity and loss of intraepidermal nerve fibers in hindpaw glabrous skin. These results suggest that activation of paracrine MCP-1/CCR2 signaling between dorsal root ganglion neurons plays a critical role in the development of paclitaxel CIPN, and targeting MCP-1/CCR2 signaling could be a novel therapeutic approach. PERSPECTIVE CIPN is a severe side effect accompanying paclitaxel chemotherapy and lacks effective treatments. The current study suggests that blocking MCP-1/CCR2 signaling could be a new therapeutic strategy to prevent or reverse paclitaxel CIPN. This preclinical evidence encourages future clinical evaluation of this strategy.

The anterior cingulate cortex and pain processing

The neural network that contributes to the suffering which accompanies persistent pain states involves a number of brain regions. Of primary interest is the contribution of the cingulate cortex in processing the affective component of pain. The purpose of this review is to summarize recent data obtained using novel behavioral paradigms in animals based on measuring escape and/or avoidance of a noxious stimulus. These paradigms have successfully been used to study the nature of the neuroanatomical and neurochemical contributions of the anterior cingulate cortex (ACC) to higher order pain processing in rodents.

Persistent chemoneuropathy in patients receiving the plant alkaloids paclitaxel and vincristine

PurposeChemoneuropathy remains a painful, burdensome complication of cancer treatment for patients receiving a range of chemotherapeutics, yet the cause and persistence of this condition are not fully documented. This study was designed to quantify the longevity of and contributions to neuropathy following treatment with the plant alkaloids paclitaxel and vincristine.MethodsQuantitative sensory testing was conducted approximately 18 months apart on 14 patients, seven of which had been treated with paclitaxel and seven with vincristine and compared to data from 18 healthy control subjects. In addition, skin biopsies were obtained to investigate changes in the density of Meissner’s corpuscles and epidermal nerve fibers (ENFs), the loss of which is thought to contribute to multiple forms of neuropathy.ResultsImpairments in motor skills, as measured by a grooved peg-board, were found. Deficits in touch detection were observed using von Frey monofilaments, as were changes in sharpness detection using a weighted needle device. Using a Peltier device, warmth and heat detection were impaired. These deficits were consistent across time. Remarkably, the average length of time patients reported painful neuropathy was over four and a half years. Skin biopsies were found to be deficient in Meissner’s corpuscles and ENFs.ConclusionsThe combination of widespread deficits in sensory testing and decreases in skin innervation for cancer patients receiving paclitaxel or vincristine document a persistent polyneuropathy which severely impacts these patients. Decreases in Meissner’s corpuscles and ENFs indicate a possible mechanism for the neuropathy.

Follow-up psychophysical studies in bortezomib-related chemoneuropathy patients

UNLABELLED Many frontline chemotherapeutic agents produce robust neuropathy as a dose-limiting side effect; however, the persistence of chemotherapy-related sensory disturbances and pain are not well documented. We have previously investigated the qualities of bortezomib-induced pain, and now seek to determine the ongoing nature of this pain. Twenty-six control subjects and 11 patients who had previously been treated with bortezomib and who were experiencing ongoing pain consented to recurring quantitative sensory testing. A pilot immunohistochemistry study of skin innervation was also performed on patient-obtained biopsies. Psychophysical testing in patients revealed persistent changes including decreased skin temperature in the area of pain, diminished touch and sharpness detection, increased pegboard completion times, and decreased sensitivity to skin heating. Additionally, the intensity of pain, as captured by the use of a visual analog scale and pain descriptors, was reported by patients to be unchanged during the retest despite similar morphine equivalent daily doses. The patient skin biopsies displayed a marked decrease in the density of epidermal nerve fibers and Meissners corpuscles. These results signify a persistent and severe impairment of Aβ, Aδ, and C fibers in patients with chronic bortezomib-induced chemoneuropathy. Further, this study reports a loss of both epidermal nerve fibers and Meissners corpuscles. PERSPECTIVE The results of this article indicate a persistent, painful peripheral neuropathy in patients treated with bortezomib. Pilot data indicates a loss of nerve fibers innervating the area of pain. This is the first paper to address the persistence, and potential contributing factors, of bortezomib chemoneuropathy.

Alterations in attentional mechanisms in response to acute inflammatory pain and morphine administration

Research indicates that pain negatively impacts attention; however, the extent of this impact and the mechanisms of the effect of pain on normal attentional processing remain unclear. This study 1) examined the impact of acute inflammatory pain on attentional processing, 2) examined the impact of morphine on attentional processing, and 3) determined if an analgesic dose of morphine would return attentional processing to normal levels. Male Sprague-Dawley rats were trained on the 5 choice serial reaction time task (5CSRTT), a test commonly used to assess the attentional mechanisms of rodents. Animals were injected with saline or 1, 3, or 6 mg/kg of morphine. Twenty minutes later, animals received a formalin (or saline) injection into one hind paw to induce an inflammatory condition and were then immediately tested in the 5CSRTT. The results show that the formalin injection significantly impaired performance, as measured by an increase in the number of trials in which the animal failed to attend to the task. Likewise, a high dose of morphine (6 mg/kg) produced similar decrements in task performance. Of primary importance is that 3 mg/kg of morphine produced analgesia with only mild sedation, and performance in the 5CSRTT was improved with this dose. This is the first study to use an animal model of acute pain to demonstrate the negative impact of pain on attention, and provides a novel approach to examine the neural correlates that underlie the disruptive impact of pain on attention.

Mechanisms involved in the development of chemotherapy-induced neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating and painful condition seen in patients undergoing treatment with common agents such as vincristine, paclitaxel, oxaliplatin and bortezomib. The mechanisms of this condition are diverse, and include an array of molecular and cellular contributions. Current research implicates genetic predispositions to this condition, which then may influence cellular responses to chemotherapy. Processes found to be influenced during CIPN include increased expression of inflammatory mediators, primarily cytokines, which can create cascading effects in neurons and glia. Changes in ion channels and neurotransmission, as well as changes in intracellular signaling and structures have been implicated in CIPN. This review explores these issues and suggests considerations for future research.

Subclinical Peripheral Neuropathy Is a Common Finding in Colorectal Cancer Patients Prior to Chemotherapy

Purpose: Of the numerous complications associated with cancer and cancer treatment, peripheral neuropathy is a deleterious and persistent patient complaint commonly attributed to chemotherapy. The present study investigated the occurrence of subclinical peripheral neuropathy in patients with colorectal cancer before the initiation of chemotherapy. Experimental Design: Fifty-two patients underwent extensive quantitative sensory testing (QST) before receiving chemotherapy. Changes in multiple functions of primary afferent fibers were assessed and compared with a group of healthy control subjects. Skin temperature, sensorimotor function, sharpness detection, and thermal detection were measured, as was touch detection, using both conventional (von Frey monofilaments) and novel (Bumps detection test) methodology. Results: Patients had subclinical deficits, especially in sensorimotor function, detection of thermal stimuli, and touch detection that were present before the initiation of chemotherapy. The measured impairment in touch sensation was especially pronounced when using the Bumps detection test. Conclusions: The patients with colorectal cancer in this study exhibited deficits in sensory function before undergoing chemotherapy treatment, implicating the disease itself as a contributing factor in chemotherapy-induced peripheral neuropathy. The widespread nature of the observed deficits further indicated that cancer is affecting multiple primary afferent subtypes. Specific to the finding of impaired touch sensation, results from this study highlight the use of newly used methodology, the Bumps detection test, as a sensitive and useful tool in the early detection of peripheral neuropathy. Clin Cancer Res; 18(11); 3180–7. ©2012 AACR.

The relationship between basal level of anxiety and the affective response to inflammation

Pain is a multidimensional experience and is modulated by a number of factors. One such factor that plays a critical role in pain modulation is anxiety. However, the influence of individual differences in anxiety on higher order pain processing in rodents remains unclear. Therefore, the purpose of this study was to identify animals that have baseline levels of high and low anxiety using the elevated plus maze and then measure pain threshold and place escape/avoidance responding (a measure of pain affect) in the animals. As expected, there was a range of baseline behavior in the elevated plus maze that was used to separate animals into high and low anxiety groups. Following carrageenan injection, both groups of animals developed a similar degree of mechanical hypersensitivity and both groups showed similar place escape/avoidance behavior. These findings suggest that individual differences in baseline anxiety levels do not significantly contribute to the development of mechanical sensitivity and do not modulate higher order pain processing related to pain affect and motivation.

Subclinical Peripheral Neuropathy in Patients With Multiple Myeloma Before Chemotherapy Is Correlated With Decreased Fingertip Innervation Density

PURPOSE The goal in this study was to determine the incidence of subclinical neuropathy in treatment-naive patients with multiple myeloma (MM) with no history of peripheral neuropathy using quantitative sensory tests (QSTs) and its correlation with innervation density of the extremities using noninvasive laser reflectance confocal microscopy. PATIENTS AND METHODS QST results were collected for 27 patients with a diagnosis of MM and compared with data collected from 30 age- and sex-matched healthy volunteers. Skin temperature, sensorimotor function (grooved pegboard test), and detection thresholds for temperature, sharpness, and low-threshold mechanical stimuli (von Frey monofilaments and bumps detection test) were measured. Meissners corpuscle (MC) density in the fingertips was assessed using in vivo laser reflectance confocal microscopy. RESULTS Patients showed a high incidence (> 80%) of ≥ one subclinical QST deficit. These included increased von Frey, bumps, and warmth detection thresholds as compared with healthy volunteers. Patients also showed increases in cold pain, sensorimotor deficits (grooved pegboard test), and higher overall neuropathy scores. MC density was significantly lower in patients than controls and showed significant inverse correlation with bumps detection threshold. CONCLUSION Patients with MM commonly present with sensory and sensorimotor deficits before undergoing treatment, and these deficits seem to result from disease-related decreases in peripheral innervation density.