Canada is immersed in an opioid crisis. In 2019, 10 Canadians per day died due to opioid overdose. Worryingly, these trends appear to be exacerbated by the COVID-19 pandemic. Since March 2020, rates of fatal opioid overdose have doubled in many parts of the country. Unfortunately, existing strategies to manage opioid addiction are minimally effective. Some 65% of those seeking treatment for opioid addiction will relapse within a month. This is especially dangerous since the risk of death is higher when opioids are used after a period of abstinence. Novel, effective strategies that reduce the likelihood of relapse are needed to improve health outcomes for those suffering from opioid addiction.

Brexpiprazole is an atypical antipsychotic drug currently approved for the treatment of schizophrenia. It acts primarily as a partial agonist at the dopamine receptor. Partial agonists are interesting drugs. Agonists are drugs that bind and activate a specific receptors (antagonists are drugs and block receptors from being activated). Full agonists, like the neurotransmitter dopamine, bind to the dopamine receptor and cause full activation of that receptor. Brexpiprazole, on the other hand, is a partial agonist. That means when it binds to the dopamine receptor, it can only ever partially activate that receptor – even at the highest doses of the drug. When brexpiprazole is alone, it is free to bind the dopamine receptors, but because it only ever partially activates the dopamine receptors, it causes a mild activation of the dopamine system (a ‘tickle’, if you will). This can be advantageous, because while low dopamine levels are associated with depression and loss of pleasure, too much dopamine signalling is associated with psychosis (like in diseases, such as schizophrenia). Brexpiprazole is pretty good at stabilizing the dopamine system, without unwanted side effects, like hallucinations and psychosis. The interesting thing about partial agonists, however, is that they can act as antagonists when in the presence of a full agonist (like dopamine). This is because if brexpiprazole and dopamine are both present, they are competing for binding at the same receptor (those dopamine receptors). If brexpiprazole is bound to a dopamine receptor, dopamine cannot bind and fully activate the receptor. Therefore, brexpiprazole will reduce (or antagonize) the effects of dopamine.

Dopamine signalling in the brain has been tied to many aspects of opioid addiction. For example, opioids, like heroin or fentanyl, cause a dramatic rise in dopamine levels in the brain. This rise in dopamine contributes to the reinforcing or ‘addicting’ properties of drugs, such as opioids. Chronic opioid use, on the other hand, leads to a paradoxical drop in resting dopamine levels (in the absence of drugs of abuse). This ‘hypo’ dopamine state is tied to negative feelings and anhedonia that contribute to the unpleasant constellation of symptoms associated with opioid withdrawal. Brexpiprazole, being a partial agonist at the dopamine receptor, can theoretically improve both of these aspects in opioid dependence. It will reduce the effects of drug-evoked dopamine release. But, it will also gently activate the dopamine system when dopamine levels are low (like during withdrawal).

We tested this hypothesis in our animal model of opioid dependence. Male and female adult mice were treated twice daily with escalating doses of the opioid, morphine. This treatment causes the classical symptoms of opioid dependence, such as analgesic tolerance. It also leads to withdrawal when the drug treatment stops. We treated morphine dependent mice with or without brexpiprazole. We found that brexpiprazole was effective at blocking the rewarding effects of morphine. It also attenuated relapse behaviour during a forced abstinence period and improved some symptoms of opioid withdrawal, including hyperalgesia (increased pain). These results indicate that brexpiprazole is effective at mitigating some of the dopamine-dependent behaviours associated with chronic opioid use. It provides strong preclinical evidence that this drug will be effective at promoting abstinence rates in those seeking treatment for opioid use disorder.

This paper was published in the journal Neuropharmacology in April of this year. The project was led by our PhD Student, Julia Nickols and in collaboration with Dr. Serdar Dursun, Professor and Psychiatrist at the University of Alberta. This work was funded by the Canadian Research Initiative on Substance Misuse (CRISM).

You can find a link to the paper here or download it below.

Read our new paper out now in the journal Pain.

Multiple sclerosis (MS) is an autoimmune disease characterized by chronic inflammation and demyelinating lesions within the central nervous system. Canada has one of the highest rates of MS in the world with 1 in 385 Canadians currently diagnosed with MS. Chronic pain is a highly prevalent symptom associated with MS, affecting 50-80% of patients over the course of their disease. Unfortunately, MS-associated chronic pain responds poorly to currently available analgesics, contributing to overall disease burden and reduced quality of life. The development of novel therapies for MS-associated pain is urgently needed to manage this disease.

Chronic pain is defined by multiple structural and functional changes within the central nervous system. While adaptations within nociceptive spinal and sensory circuits have rightfully received focused attention over the years, new research is beginning to explore how changes within affective circuitry can contribute to both the sensory and affective symptoms of autoimmune-associated pain. Patients with MS develop anatomical and functional changes in affective brain regions, particularly the amygdala. We also know that affective circuits can exacerbate the perception of pain, either through amplification of pain signals to the brain or by interfering with endogenous pain control. How the affective system changes in MS to exacerbate the sensory and affective symptoms of autoimmune-associated pain remains unclear.

In this study, we demonstrated that a mouse model of MS results in functional changes in central amygdala activity. This altered activity correlated with increased pain behaviour and impaired morphine analgesia, specifically in females. This altered activity also coincided with robust inflammation within the central amygdala. Inducing inflammation focally within the central amygdala of healthy mice was sufficient to evoke pain behaviours seen in our chronic pain models. This suggests that inflammation within the central amygdala impairs nociceptive signaling and contributes to pain hypersensitivity in this model.

This project was lead by our graduate student, Zoë with help from then undergraduate students Holly and Christian. Zoë recorded a fantastic summary of this project for the journal. You can listen to it here.

We are thrilled to announce that the Taylor lab has received 5 years of funding from the Canadian Institutes for Health Research (Project Scheme).

One of the hallmarks of autoimmune inflammation is chronic persistent pain in the absence of tissue damage or injury. Recently, the amygdala has emerged as a critical regulator of pain perception and control. To date, no research has examined how autoimmune inflammation alters amygdala activity, and whether changes in the amygdala contribute to pain hypersensitivity and opioid tolerance in this condition. Our research program will describe how cells in the amygdala respond to pain and analgesic stimuli following autoimmune inflammation. We then test strategies to restore amygdala function in order to improve pain and affective symptoms. These results will explore novel circuits contributing to pain hypersensitivity and improve our understanding of mechanisms driving chronic inflammatory pain.

We are grateful to CIHR and the Canadian taxpayers for supporting this work.

The Taylor lab has published a new study out now in the Journal of Neuroscience Research. Here we used a couple of really powerful mouse models to examine why kappa opioid receptor agonists work less well in females. Kappa agonists are currently being developed as new, non-addicting treatments for chronic pain and itch. Understanding how they work in males and females is critical if they are to be tested in human clinical trials.

A number of previous studies have examined kappa opioid receptor sex differences by measuring or manipulating gonadal sex hormones (namely, estrogen and testosterone). While this can useful to determine the effect of circulating hormones during adulthood, this approach cannot examine the effect of gonadal hormones during development. This approach also cannot rule out the effect of the complement of genes expressed on the sex chromosomes (either the X or Y chromosome), because sex chromosomes are always associated with their accompanying sex hormones (Two X chromosomes with estrogen,  one Y chromosome with testosterone).

Kappa opioid receptor (KOR) agonists are known to have a notable sex difference; however, the biological basis for this sex difference remained elusive. Previous work relying on surgical or chemical manipulation of gonadal hormones have produced conflicting results on the relative contribution of gonadal hormones to the KOR sex difference.
Here, we were able to show that sex chromosomes (and particularly the X chromosome) contribute significantly to the KOR sex difference. This discovery carries meaningful
clinical implications given KOR agonists are currently being developed as novel analgesics, and women are significantly more likely to require pain treatments in their lifetime.

Here, we use a mouse model (four core genotypes) where by we manipulate the activity of the testes-determining gene, SRY (the gene found on the Y chromosome responsible for testes development in males). Removal of the SRY gene from the Y chromosome generates XY animals without testes. In fact, in absence of the SRY gene, mice develop ovaries and are gonadally “female” (they look and act like females, and are housed with normal XX mice). Conversely, if we take the SRY gene and insert it in the genome of an XX mouse, this generates XX mice that develop testes and are gonadally “male”. Comparing XX “males” (i.e. testes and testosterone) and “females” with XY males and “females” allows us to quickly determine whether a specific behavior or trait is mediated by either sex chromosomes or hormones (or both!). Here, we found that kappa opioid receptor analgesia is driven largely by the makeup of sex chromosomes, rather than gonadal hormones. Mice with 2X chromosomes were less responsive to kappa opioid receptor analgesia than mice with the Y chromosome, independent whether they had male or female gonads.

While this model is instrumental in isolating the sex chromosome and gonadal effects, it cannot tell us which sex chromosome is responsible for the difference (is it the two X chromosomes or the absence of the Y chromosomes that is important?). To answer this question, we used another mouse model call the XY*. Here, the number of X and Y chromosomes are varied. The genetics behind this model is complex; however, it essentially generates 4 permutations of sex chromosomes: XX, XY, XO (“female” with only 1 X chromosome), and XXY (“male” with two X chromosomes). This allows us to determine whether the sex difference is due to the presence or absence of either the X or Y chromosome. Here, we found that mice with two X chromosomes (either XX or XXY) had lower kappa opioid receptor analgesia. This means that the loss of kappa analgesia is due to genes expressed on the X chromosome.

These are very exciting findings that lead to many more questions. Which genes on the X chromosome are responsible? Could we temporarily make females more like males (genetically speaking) to help improve kappa analgesia in the clinic? These are ongoing experiments in our lab – so stay tuned!

You can find the paper on Pubmed or download here.

Our graduate student Zoë spear-headed a recent review examining the relationship between the gut microbiome, neuroinflammation, and chronic pain. Here, she considers the emerging evidence that communication between the gut microbiome and microglia drives the chronicity of pain. She reviews the current literature that supports a link between gut bacteria and central inflammation and discusses the potential mechanisms by which the gut microbiome and microglia communicate to influence the chronicity and perception of pain. Finally, she highlights gaps in knowledge, and discusses the implications for targeting gut health to improve pain outcomes in chronic pain populations.

You can access the paper via PubMed here or download direct here.

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Nature Outlook’s most recent issue is all on the opioid crisis. Here, Dr. Taylor discusses her work on opioids and the gut microbiome (article here).

Check out the full issue here.

The Taylor Lab is participating in a couple upcoming public lectures. These are great opportunities for the community to learn about our work in a fun, engaging environment.

NMHI Public Lecture, October 30th 6-9pm

First, the Neuroscience and Mental Health Institute at the University of Alberta is hosting a public lecture on the gut microbiome in health and disease. Lectures will cover what the gut microbiome is and its role in multiple sclerosis, spinal cord injury, and addiction. Dr. Taylor will be presenting her work on the gut microbiome and opioid use disorders. Lectures will be followed by an open question period.

This lecture is free and happens October 30th at 6pm in the Allard Lecture Hall in the Katz Building.

The Taylor lab will also be represented at the Telus World of Science Dark Matters Event. This is in adult-only event with a DJ, open bar, and local guest experts with interactive displays. This years theme is “Science of Drugs”, and the Taylor lab will be talking about how drugs interact with the brain and how we study them in the lab. 

Telus World of Science: Dark Matters, October 3, 6-10pm

The event is October 3rd. Get your tickets here!

The Taylor lab was recently awarded a Canadian Foundation for Innovation JELF award that will help establish a cutting edge Pain and Addiction Laboratory at the University of Alberta.

This award will be used to purchase equipment for an advanced rodent behavioural testing facility, as well as imaging and molecular tools that will help us investigate underlying mechanisms contributing to chronic pain and opioid addiction.

Our lab was recently profiled in Folio. You can read it here.

We wrote a commentary on the recent paper looking at learned conditioned pain sensitivity in male and females (Martin et al). This study describes a novel paradigm to investigate the intersection between memory, pain, and stress, and demonstrates that placing mice or humans in an environment that was previously associated with pain can lead to heightened sensitivity in the absence of a painful stimulus. We comment on the implications of these results with regards to pain in men and women.

Well done, Zoe, a first-year Taylor lab Master’s student, for taking the lead on this effort. You can read the full commentary here.