Depression during the perinatal time period is the most common medical condition related to pregnancy and childbirth. Based on previous research, this condition can have negative sequelae for mothers, their offspring, families and the community. Therefore, studies are needed to better understand risk factors and health outcomes among women with depression and the health outcomes among children born to mothers with depression. We examined rurality as a risk factor for depression during the perinatal time period using data from the 2016 Pregnancy Risk Assessment Monitoring Survey (aim one). We found women who resided in rural communities, as defined by their individual states, had an increase in the odds of depression during the perinatal period by 21% (OR: 1.21; 95% CI 1.05,1.41) when compared to women who resided in urban communities. Based on the results from this study, future studies are warranted to examine mediators of this relationship to develop effective public health and clinical interventions. Next, we examined the association between perinatal mental health conditions and postpartum prescription opioid use using private insurance claims data of women who delivered a baby in the state of Iowa 2005 to 2016 (aim two). Overall 38.63% of the women in our study filled at least one opioid prescription and 5.88% filled at least two prescriptions in the first 90 days postpartum. A significant interaction of having a perinatal mental health condition and delivery mode was observed for at least one (p=.04) and at least two opioid fills (<.0001). The presence of a mental health condition among women who delivered vaginally increased their odds of filling at least one opioid fill by nearly 50% (OR: 1.48 95% CI 1.35, 1.63) and by almost 20% (OR: 1.19 95% CI: 1.00, 1.43) among women with a cesarean delivery. A mental health condition significantly increased the odds of filling at least two opioid prescriptions among women with a vaginal or cesarean delivery by 2.78 (95% CI: 2.32-3.33) and 1.66 (95% CI: 1.40,1.98). Based on findings from this study, more research is needed to improve our understanding of the relationship between perinatal mental health and prescription opioid use. Finally, the association between perinatal depression and attention deficit hyperactivity disorder (ADHD) use was examined using private insurance claims data from mother-child pairs from the state of Iowa (aim three). Children were born during years 2004 through 2015. In our study children born to mothers with perinatal depression were at an increased odds of ADHD diagnosis by 170% (OR: 2.70; 95% CI 2.06, 3.55). We also evaluated how timing of depression (during pregnancy vs. postpartum) influenced the odds of ADHD diagnosis. While we found children born to mothers with depression during pregnancy and postpartum had an increased risk of ADHD diagnosis, we observed children exposed to depression during fetal development had the greatest risk overall. Research is needed to better understand the mechanisms of risk between perinatal depression and ADHD risk in offspring. Additionally, due to low power we were not able to evaluate how treatment of depression during pregnancy or postpartum may influence childhood outcomes, therefore more studies are needed in this area. Overall, findings from each study illustrate the importance of maternal mental health and how a mental health condition during the perinatal period can influence maternal and child health outcomes. Future prospective population-based studies are needed to better understand the etiologies of perinatal mental health conditions and how such conditions can influence outcomes for maternal and child health. Results from future studies have the potential to shift clinical practice to improve prevention and intervention in turn improving overall maternal and child health outcomes.

Blake Lapin's senior thesis, Durability of Bone, is a five-part collection of poems written, edited, and compiled under the mentorship of Henri Cole. Themes include loss, love, travel, disability, and home.

New drug epidemics often unleash punitive campaigns to end them- highlighted by the 1980’s drug wars. However, the opioid crisis has been met with public-health driven policies, like clean needle programs and community-based substance abuse therapy. This thesis asks why policy responses to the opioid crisis are so different than those of the War on Drugs. First, as the cost of the drug war became clearer, policy makers across the political spectrum became less inclined to wage a new punitive war against opioids, especially as public-health responses proved to be more effective while also less costly. Second, the demographics of those addicted to opioids is different than those who were addicted to crack cocaine. The brunt of War on Drugs policies was felt by those in the lowest socioeconomic brackets and perpetuated poverty in low-income communities. Today’s softer approaches have been informed by a greater percentage of middle- to upper-class individuals affected by the opioid crisis. Third, as opioids have legitimate medical purposes, they are harder to demonize or ban, rendering it more difficult to declare total war against them. Further, the influence opioid manufacturers have has made policy makers less inclined to declare war, taking supply-side action. Public-health driven policies and policies that minimize supply-side action against pharmaceutical opioid manufacturers are duplicate representations of the United States’ departure from War on Drug tactics. As long as the “medical model” of health care, which emphasizes drugs, medical treatment, and surgery is ingrained in society and the economy, these patterns will continue.

In October 2017, the United States government declared a state of public health emergency in response to the burgeoning prescription opioid epidemic. Opioid analgesics are the gold standard of therapy for moderate to severe pain, but their clinical utility is greatly limited by analgesic tolerance – a primary driver of diminished pain control and opioid dose escalations. Integral in this process are primary afferent sensory neurons in dorsal root ganglia (DRG), the first-order components of nociceptive sensation. With surmounting evidence that morphine and other narcotics can alter gut microbial composition and promote bacterial translocation to other tissues, a question arises of whether the secondary release of bacterial products and pro-inflammatory cytokines can modulate antinociceptive tolerance development. This dissertation examines how gut bacteria depletion with antibiotics modulates the pharmacodynamic properties of chronic morphine in mice. Utilizing a “top-down” experimental approach, this is characterized at the whole-animal, single-cell, and molecular level via behavioral assays of antinociception, whole-cell patch-clamp recordings in DRG neurons, and analysis of tetrodotoxin-resistant (TTX-R) Na+ channel kinetics, respectively. Our findings collectively indicate that the gastrointestinal microbiome is an important modulator of antinociceptive tolerance development with chronic morphine administration.

Paclitaxel, vincristine, oxaliplatin, and bortezomib are cancer chemotherapy drugs with adverse effects that include chemotherapy-induced neuropathic pain (CINP) as well as depression of behavior and mood. In the clinical setting, opioids are often used concurrently with or following chemotherapy to treat pain related to the cancer or CINP, but repeated opioid exposure can also increase the risk of opioid abuse. This dissertation evaluated the effect of chemotherapy treatment on motivated behaviors and opioid reward in rats. The main findings of this evaluation are as follows: (1) Chemotherapy, at doses that produce robust and sustained mechanical hypersensitivity produce only weak or nonexistent depression of positively reinforced operant responding maintained either by electrical brain stimulation in an assay of intracranial self-stimulation or by food pellets in an assay of food-maintained responding. (2) There was no correlation between the expression of mechanical hypersensitivity and depression of motivated behaviors across individual animals, suggesting that these two effects of chemotherapy do not share common mechanisms of action. (3) Mechanical hypersensitivity, but not behavioral depression could be reversed with morphine. (4) The class of chemotherapeutic used in preclinical models is a determinant of the severity of effects on neuropathy-related endpoints and on the time course of these effects. (5) Chemotherapy does not protect against the rewarding effects of repeated morphine administration and does not alter the time course of the enhancement of reward with repeated morphine exposure. These findings suggest that administration of chemotherapy to rats induces mechanical hypersensitivity while failing to decrease behaviors dependent on mesolimbic dopamine signaling or protecting against morphine abuse-related effects. While apparent that chemotherapy can produce peripheral neuropathy, the data in this dissertation does not support the hypothesis that chemotherapy can produce behavioral depressant manifestations of chemotherapy-induced neuropathic pain (CINP) in rats.

Studies on repeated exposure to opioids have been carried out for decades yet the mechanisms for certain phenomena such as tolerance are still not fully understood. Furthermore, different medications, such as frequently prescribed benzodiazepines, or different disease states, such as HIV, have their own effects and interactions with chronic opioid exposure that are not fully understood. The overall objective of this dissertation was to investigate the complexities of chronic opioid exposure and how different disease states and medications may modulate the effects of chronic opioids. Our findings demonstrate that the administration of diazepam, at doses that are not antinociceptive or have any motor effects, reverse both antinociceptive and locomotor tolerance to orally active opioids. These doses of diazepam did not potentiate the acute effects of these prescription opioids. We also found that HIV-1 Tat expression significantly attenuated the antinociceptive potency of acute morphine in non-tolerant mice while not significantly altering the antinociceptive tolerance to morphine. Consistent with this, Tat attenuated withdrawal symptoms among morphine-tolerant mice. Pretreatment with maraviroc, a CCR5 antagonist blocked the effects of Tat, reinstating morphine potency in non-tolerant mice and restoring withdrawal symptomology in morphine-tolerant mice. Protein array analyses revealed only minor changes to cytokine profiles whether morphine was administered acutely or repeatedly; however, 24 h post repeated morphine administration, the expression of several cytokines was greatly increased. Tat further elevated levels of several cytokines and maraviroc pretreatment attenuated these effects. With the understanding that gap junctions may be involved in both HIV-Tat effects on opioid antinociception as well as tolerance, we investigated the role of gap junctions in opioid antinociceptive tolerance. We observed that carbenoxolone, a gap junction inhibitor, administered systemically attenuated the development of opioid antinociceptive tolerance. Furthermore, we observed a small percentage of carbenoxolone in brain tissue compared to the amount found in blood, suggesting a peripheral site of action. Finally, we show preliminary evidence that in vivo administration of carbenoxolone is able to attenuate tolerance to morphine in DRG neurons.

The increase in heroin use is one factor contributing to the current opioid epidemic in the United States. There are three Food and Drug Administration (FDA) approved medications for the treatment of opioid use disorder (OUD), and these include agonist (i.e. methadone and buprenorphine) and antagonist (i.e. naltrexone) therapies. Although these medications are effective for some patients, regulatory constraints for agonist therapies limit access and patient compliance for naltrexone is poor. The development of new therapies, such as immunopharmacotherapies, for the treatment of OUD is a priority for the National Institute of Drug Abuse. A heroin immunopharmacotherapy, or vaccine, produces heroin selective antibodies that bind to and sequester heroin in the periphery. One formulation of a heroin-tetanus toxoid (TT) conjugate vaccine has shown promise in preclinical studies in mice in monkeys but has not been fully assessed to determine independent variables that might impact vaccine effectiveness such as heroin route of administration, species of animal or abuse-related behavioral endpoints. Chapter II of this dissertation aimed to determine effectiveness and selectivity of the heroin-TT conjugate vaccine to alter the antinociceptive effects of subcutaneous and intravenous heroin in male and female rats. In addition, maximal vaccine effects were compared to effects of a positive control naltrexone. Vaccine effectiveness to reduce heroin antinociception was selective, but effectiveness did not depend on route of administration. Furthermore, maximum effects were less than those seen with a clinically meaningful dose of naltrexone. Combining the vaccine with naltrexone enhanced the effectiveness of naltrexone to block the antinociceptive effects of heroin. Chapter III determined vaccine effectiveness and selectivity to block heroin’s discriminative-stimulus effects in nonhuman primates and compared maximal effects produced by vaccine and naltrexone. The heroin vaccine weakly but selectively reduced the abuse-related subjective-like effects of heroin in one of two monkeys. However, chronic naltrexone treatment nonselectively antagonized the abuse-related effects of both heroin and fentanyl, and naltrexone effects were more robust than those of the vaccine. Chapter IV established a translational procedure to assess candidate medication effects on the reinforcing effectiveness of heroin in a heroin versus food choice procedure in rats. In the procedure, rats choose between a liquid food reinforcer and ascending doses of heroin in a 5-component choice procedure. Heroin versus food choice was found to be sensitive to an environmental manipulation of altering response requirement for both reinforcers. Chronic buprenorphine decreased heroin choice, consistent with its FDA-approved indication for treating OUD. Collectively, these data suggest that the current formulation of the heroin-TT conjugate vaccine may not be as effective as naltrexone at decreasing heroin use. However, one potential indication the vaccine may be useful for is as an adjunctive therapy to clinically available agonist or antagonist medications and a heroin versus food choice procedure in rodents would be one way to full assess this preclinically.

The type of cancer pain management used may have an effect on the quality of life (QOL) of cancer patients. Researchers have determined that cancer patients are inadequately treated for pain and pain management is an essential determinant of patient survivability and QOL. Numerous clinical studies have been accomplished concerning opioid administration and noncancer and cancer pain management exist. Previous studies have examined the relationship between cannabinoid products, noncancer pain, cancer pain, and related QOL for patients but have not focused on the QOL of cancer patients while also moderating for gender. These relationships were investigated using the health belief model. The cancer pain management treatments (opioids and/or marijuana [cannabis]) and QOL, measured with World Health Organization Quality of Life Survey (WHOQOL-BREF), of 236 cancer patients were analyzed using analysis of variance (ANOVA), planned contrasts, post hoc tests, and moderated ANOVA (PROCESS tool) in the causal-comparative research. Research findings indicated significant benefit in cancer patient physical and psychological QOL in participants using marijuana when compared to participants using opioids and physical QOL for participants using marijuana over participants using both opioids and marijuana combined. Enhanced pain management options for cancer patients in order to reduce opioid side effects, increase pain treatment effectiveness, and improve patient QOL could yield positive social change. Growing rates of opiate addiction, abuse, and mortality are public health concerns and cannabis may be an effective pain treatment to reduce these social costs. This research may be of use to legislators considering rescheduling marijuana to less than Schedule I.

Living organisms are capable of producing novel terpenoids with both remarkable ease and great selectivity. Many of these natural products exhibit significant biological activity useful for treatment of human diseases, but isolation of highly sought chemicals often results in only minute quantities. Consequently, extraction of these potential therapeutics from natural sources becomes an unrealistic method for obtaining enough material for a thorough biological evaluation, and so synthesizing these compounds becomes essential. Synthesis of terpenoids as potential therapeutics requires exceptional selectivity, especially when corresponding isomers elicit a contrasting biological response. The necessity for such selective syntheses along with the inherent structural complexities of terpenoids, often presents a number of significant challenges for the synthetic chemist. Isolation of the terpenoids pawhuskins A–C and petalostemumol from Dalea purpurea was reported by Belofsky in 2004, and of the collected compounds pawhuskin A was found to exhibit the most significant activity in an opioid receptor assay in vitro. Natural pawhuskin A was extracted from “Purple Prairie Clover” in only a 39 mg quantity and therefore syntheses of the natural product along with several analogues were pursued. Two of the synthesized analogues demonstrated greater potency than pawhuskin A, and interestingly these two isomeric derivatives were found to be selective for two different opioid receptors. However, the synthetic route utilized to form these two derivatives was not very selective for either isomer, and thorough purification proved challenging. Ergo, an alternative approach was sought to ensure the purity of these potential therapeutics. Parallel syntheses affording high selectivity for the key isomeric intermediates as well as a third regioisomer have been developed. The new isomeric intermediate also allowed the synthesis of two new analogues. This work is described in this report along with the formation of additional pawhuskin derivatives. The activity of these analogues as opioid receptor modulators also will be discussed.

The experiments reported in this thesis studied the contributions of opioid and NMDA receptors to predictive fear learning, as measured by freezing in the rat. The first series of experiments (Chapter 2) used a within-subject one-trial blocking design to study whether opioid receptors mediate a direct action of predictive error on Pavlovian association formation. Systemic administrations of the opioid receptor antagonist naloxone or intra-vlPAG administrations of the selective μ-opioid receptor antagonist CTAP prior to Stage II training prevented one-trial blocking. These results show for the first time that opioid receptors mediate the direct actions of predictive error on Pavlovian association formation. The second series of experiments (Chapter 3) then studied temporal-difference prediction errors during Pavlovian fear conditioning. In Stage I rats received CSA ?? shock pairings. In Stage II they received CSA/CSB ?? shock pairings that blocked learning to CSB. In Stage III, a serial overlapping compound, CSB → CSA, was followed by shock. The change in intra-trial durations supported fear learning to CSB but reduced fear of CSA, revealing the selective operation of temporal-difference prediction errors. This bi-directional change in responding was prevented by systemic NMDA receptor antagonism prior to Stage III training. In contrast opioid receptor antagonism differentially affected the learning taking place during Stage III, enhancing learning to CSB while impairing the loss of fear to CSA. The final series of experiments (Chapter 4) then examined potential neuroanatomical loci for the systemic effects reported in Chapter 3. It was observed that intra-BLA infusion of ifenprodil, an antagonist of NMDA receptors containing the NR2B subunit, prevented all learning during Stage III, whereas intra-vlPAG infusion of the μ-opioid receptor antagonist CTAP facilitated learning to CSB but impaired learning to CSA. These results are consistent with the suggestion that opioid receptors in the vlPAG provide an important contribution to learning. Importantly, this contribution of the vlPAG is over and above its role in producing the freezing conditioned response. Furthermore, the findings of this thesis identify complementary but dissociable roles for amygdala NMDA receptors and vlPAG μ-opioid receptors in predictive fear learning.