Effectiveness of Duloxetine on Oxaliplatin-induced Allodynia and Hyperalgesia in Rats.

Development of painful oxaliplatin-induced peripheral neuropathy (OIPN) is a major problem in people who receive oxaliplatin as part of cancer treatment. The pain experienced by those with OIPN can be seriously debilitating and lead to discontinuation of an otherwise successful treatment. Duloxetine is currently the only recommended treatment for established painful OIPN recommended by the American Society of Clinical Oncology, but its preventative ability is still not clear. This study examined the ability of duloxetine to prevent signs of chronic OIPN in female (n = 12) and male (n = 21) rats treated with the chemotherapeutic agent oxaliplatin. Using an established model of OIPN, rats were started on duloxetine (15 mg) one week prior to oxaliplatin administration and continued duloxetine for 32 days. Behavioral testing for mechanical allodynia and mechanical hyperalgesia was done with selected von Frey filaments. Significant posttreatment differences were found for allodynia in female (p = .004), but not male rats. Duloxetine was associated with significant differences for hyperalgesia in both female (p < .001) and male (p < .001) rats. These findings provide preliminary evidence of the preventative effects of duloxetine on both oxaliplatin-induced allodynia and hyperalgesia in male and female rats, with a difference noted in response between the sexes.

Variability of DNA Repair and Oxidative Stress Genes Associated with Worst Pain in Breast Cancer Survivors on Aromatase Inhibitors.

Pain is a problem affecting women with breast cancer (HR+BrCa) receiving aromatase inhibitor (AI) therapy. We investigated the relationship between single-nucleotide polymorphisms (SNPs) in DNA repair and oxidative stress genes and perceived worst pain after 6 months of AI therapy. We explored 39 SNPs in genes involved in DNA repair (ERCC2, ERCC3, ERCC5, and PARP1) and oxidative stress (CAT, GPX1, SEPP1, SOD1, and SOD2) in women with HR+BrCa receiving adjuvant therapy (AI ± chemotherapy; n = 138). Pain was assessed via the Brief Pain Inventory. Hurdle regression was used to evaluate the relationship between each associated allele and (1) the probability of pain and (2) the severity of worst pain. ERCC2rs50872 and ERCC5rs11069498 were associated with the probability of pain and had a significant genetic risk score (GRS) model (p = 0.003). ERCC2rs50872, ERCC5rs11069498, ERCC5rs4771436, ERCC5rs4150360, PARP1rs3219058, and SEPP1rs230819 were associated with the severity of worst pain, with a significant GRS model (conditional mean estimate = 0.45; 95% CI = 0.29, 0.60; p < 0.001). These results suggest DNA repair and oxidative stress pathways may play a role in the probability of pain and the severity of worst pain. As healthcare delivery moves towards the model of precision healthcare, nurses may, in the future, be able to use these results to tailor patient care based on GRS.

Symptom Science: Omics and Response to Non-Pharmacological Interventions.

Incorporating omics into non-pharmacological intervention research design could provide a better understanding of the variability in response to these interventions. It would also provide evidence for precision-based non-pharmacological interventions, including interventions focused on symptoms. The purpose of this manuscript was to present examples of studies that have used omics to examine response to non-pharmacological intervention. Using the interventions of exercise, diet (related to obesity), cognitive based therapy, and alternative mind-body practices (meditation, yoga, and tai chi), PubMed was searched to identify studies that incorporated genomic or other omic approaches as part of a non-pharmacological intervention. The review identified genes associated with the effectiveness of each of the interventions. Although there were no genes that were associated with all four interventions, there were nine genes that were the focus of more than one intervention (ACE, BDNF, COMT, CXCL8, IL6, SL6A4, TNF, GSTM1, PTGER3). All nine of these genes were either directly or indirectly biologically related to one another, suggesting that this cadre of genes could serve as an initiation point for investigations using omic approaches to better understand response to non-pharmacological interventions.

The Influence of Physical Activity and Epigenomics On Cognitive Function and Brain Health in Breast Cancer.

The risk of breast cancer increases with age, with the majority of women diagnosed with breast cancer being postmenopausal. It has been estimated that 25-75% of women with breast cancer experience changes in cognitive function (CF) related to disease and treatment, which compromises psychological well-being, decision making, ability to perform daily activities, and adherence to cancer therapy. Unfortunately, the mechanisms that underlie neurocognitive changes in women with breast cancer remain poorly understood, which in turn limits the development of effective treatments and prevention strategies. Exercise has great potential as a non-pharmaceutical intervention to mitigate the decline in CF in women with breast cancer. Evidence suggests that DNA methylation, an epigenetic mechanism for gene regulation, impacts CF and brain health (BH), that exercise influences DNA methylation, and that exercise impacts CF and BH. Although investigating DNA methylation has the potential to uncover the biologic foundations for understanding neurocognitive changes within the context of breast cancer and its treatment as well as the ability to understand how exercise mitigates these changes, there is a dearth of research on this topic. The purpose of this review article is to compile the research in these areas and to recommend potential areas of opportunity for investigation.

Pain condition and sex differences in the descending noradrenergic system following lateral hypothalamic stimulation.

The lateral hypothalamus (LH) is known to modulate nociception via the descending noradrenergic system in acute nociception, but less is known about its role in neuropathic pain states. In naïve females, LH stimulation produces opposing effects of α-adrenoceptors, with α2-adrenoceptors mediating antinociception, while pronociceptive α1-adrenoceptors attenuate the effect. Whether this opposing response is seen in neuropathic conditions or in naïve males is unknown. We used a mixed factorial design to compare male and female rats with chronic constriction injury (CCI) to naïve rats, measured by Total Paw Withdrawal (TPW) responses to a thermal stimulus. Rats received one of three doses of carbachol to stimulate the LH followed by intrathecal injection of either an α1- or an α2-adrenoceptor antagonist (WB4101 or yohimbine, resp.) or saline for control. Overall, naïve rats showed a more pronounced opposing alpha-adrenergic response than CCI rats (p < 0.04). Naïve male and female rats demonstrated antinociception following α1-adrenoceptor blockade and hyperalgesia following α2-adrenoceptor blockade. Male CCI rats also showed dose dependent effects from either WB4101 or yohimbine (p < 0.05), while female CCI rats had significant antinociception from WB4101 (p < 0.05), but no effect from yohimbine. These results support the idea that peripheral nerve damage differentially alters the descending noradrenergic modulatory system in male and female rats, and notably, that female CCI rats do not show antinociception from descending noradrenergic input. These findings are suggestive that clinical therapies that recruit the descending noradrenergic system may require a different approach based on patient gender.

Anatomical evidence for lateral hypothalamic innervation of the pontine A7 catecholamine cell group in rat.

Substantial behavioral evidence exists to support the idea that the lateral hypothalamus (LH) makes axonal connection with spinally-projecting noradrenergic neurons of the A7 catecholamine cell group in the pons. Through this putative projection, the LH modulates nociception via α1- and α2-adrenoceptors in the dorsal horn. We used double-label immunocytochemistry to demonstrate that axons from the LH labeled with the anterograde tracer biotinylated dextran amine (BDA) appose tyrosine hydroxylase-immunoreactive (TH-ir) neuron profiles in the A7 area. Other pontine areas labeled with BDA included the dorsomedial tegmental area, the pontine reticular nucleus, oral part, the caudal aspect of the dorsal raphe, the periaqueductal grey and the A6 area. To confirm the findings of the brightfield experiment, we used confocal microscopy to identify axons from the LH labeled with the anterograde tracer Fluoro-Ruby co-localized with TH-ir dendrites and cell bodies in the A7 cell group. These findings provide an anatomical substrate for behavioral studies in which stimulation of the LH modifies nociception in the spinal cord via norepinephrine.