Plant biology and pain: digging deeper into the endogenous mechanisms of analgesia
Could you tell us a bit about your background and how you came to doing a postdoc at the University of Pittsburgh?
Sure! I’m originally from Calcutta, India. My journey in the U.S. started in 2012. I first came to Texas Woman’s University where I did my master’s followed by PhD in Molecular Biology. I graduated in 2019. At the end of 2018, I started looking for postdoc positions. You wouldn’t believe it, but I came across Dr. Bradley K. Taylor’s postdoc position first. He was the first person I sent my CV to, and expressed my interest in his lab! He got back to me within an hour.
Oh my gosh!
Yes! We scheduled a Skype interview followed by an in-person interview. I came to Pittsburgh for my in-person interview in January 2019, and that’s how I secured my position. I always say that it was kind of a miracle. Brad was the first person I reached out to for a postdoc position, and I finalized with him within 1.5 months.
It was meant to be!
I know, right? There are certain things that are meant to happen.
There is definitely some serendipity to science, you know… the stars align.
Definitely. I sent out two applications in Texas, but I had to withdraw them after I accepted the offer from Brad. At first, I didn’t know that they had this big pain center (Pittsburgh Center for Pain Research - PCPR) in Pittsburgh. When I came to Pittsburgh, Brad asked me, “Do you know about PCPR?”. My grad co-mentor Dr. Dayna Averitt who is an Associate Professor at Texas Woman’s University said to me, “The PCPR is one of the few centers that does intensive pain research. I’m really glad you got an offer from there!”. So yeah, that is how it all started. I am in my second year now.
Like me, you probably were just getting situated in your postdoc when COVID-19 hit.
Exactly. Everything just closed down. 2020 was really difficult. I didn’t know where I would end up. Eventually things started to settle, and now we are in a much better situation.
It is a strange feeling being in a completely new and foreign place, away from your family, but we got through it!
Congratulations on your recent publication in the Journal of Neuroscience! Could you tell us a little bit about it?
Thank you! In this paper we explored a signalling pathway of latent pain sensitization that is masked by kappa opioid receptors in the spinal cord. We tested two hypotheses. The first hypothesis was that surgical incision establishes a long-lasting activation of kappa opioid signalling that is masked by the latent sensitization by inhibiting the N-methyl-D-aspartate receptor (NMDA) receptor and adenylyl cyclase-1 (AC1) signalling in both male and female mice. The second hypothesis was that surgical incision establishes long-lasting action of kappa opioid signalling that masks latent sensitization by inhibiting downstream of cAMP targets - that is protein kinase A (PKA) and exchange proteins directly activated by cyclic AMP (Epacs) in both male and female mice. We found that long-lasting kappa opioid receptor signalling provides endogenous analgesia by inhibiting AC1 signalling in a preclinical latent sensitization model of chronic postoperative pain, and that the mechanism of postoperative pain is different in males and females. In males, it was the NMDA receptor, AC1, cAMP, Epacs, and PKA mechanisms that drove latent sensitization. In females, it was just NMDA receptor, AC1, cAMP and Epacs signalling. So basically, PKA signalling was not involved in latent pain sensitization in females, only in males. These were very striking findings.
That’s so interesting! Biological sex is such a big variable in mechanisms of pain (see earlier blog ft. Dr. Manon Bohic). Might this change the way we think about opioid use for postoperative pain?
Absolutely. When we talk about acute postoperative pain, 10-15% of individuals experience persistent pain after a range of operations like breast, coronary bypass, thoracic surgery, groin hernia repair, leg amputation, etc. Opioids are the mainstay treatment for this postoperative pain, but we are all very much aware of their caveats like addiction, dependence, tolerance, etc. Our findings support the development of AC1, PKA and Epacs inhibitors as new pharmacotherapies for chronic postoperative pain. It’s a different approach from just treating with opioids.
Were there any unexpected findings that cropped up during this project?
As I mentioned earlier, the sex difference with the PKA signalling component was really surprising. These results underscored the importance of biological sex in identifying target molecules for pain. It supports a novel male-specific mechanism for the promotion of chronic pain. The future direction is to develop PKA inhibitors, with the idea that they might be more specific to males. This also raises more questions about the underlying conditions for the development of chronic pain in females. That’s where we need to dig deeper, looking into the effects of estrus cycle as well as crosstalk between other signalling components involved in latent postoperative pain sensitization.
Can you tell us a little bit about the process of writing up the paper? How did you approach it?
All of this work started back at the University of Kentucky. Brad’s former graduate student Lilian Custodio-Patsey started the work and she and I shared first authorship. When I joined Brad’s lab it was still an incomplete project, so he assigned it to me. I completed the signalling pathway, and I tested the involvement of the NMDA receptor. I pharmacologically inhibited the NMDA receptors with antagonists and confirmed that it was involved in this signalling pathway. At the same time, I did several additional experiments that were requested by the reviewers. The good thing was that these additional experiments really strengthened the findings of this work. In terms of writing, it was a great learning experience, as this was my first writing experience with Brad. This paper honed my writing skills, critical thinking, and gave me a deeper understanding of the field of pain neurobiology. It was definitely a great step forward from my graduate work to my first published work from my postdoc. The learning curve was steep, but I really enjoyed it and I learned so much from Brad.
It's so great that you were able to get such a great paper out within less than two years of your postdoc!
Thank you! Because of COVID-19 and everything, there was a time where only a certain number of people could be in the lab, and only a certain number of people could do animal behavior experiments. As I mentioned earlier, things got delayed due to COVID-19.
For sure, any data collection done in that time came with its own unique set of challenges which makes it all the more impressive! What are the next questions that you want to answer off the back of this study?
What I’m doing now is looking into the downstream signalling pathways that the endogenous kappa opioid receptor activation keeps under remission in a preclinical postoperative pain model. I’m exploring the signalling pathway downstream of the specific NMDA receptor/Epacs signalling pathway that we talked about earlier. Identifying the components of this pathway will provide new avenues for treating postoperative pain conditions. I’m mainly exploring these signalling pathways by employing different pharmacological inhibitors and activators to see exactly which components are involved, and whether the kappa opioid receptor is masking that signalling component. Furthermore, I’m doing some genetic manipulations to determine whether latent sensitization occurs in the central or peripheral nervous system or both!
You also published a review recently in the International Journal of Molecular Sciences, which is an open access MDPI journal. How was the process of preparing that for publication?
This review was really interesting to write, and it is all about curcumin. It has no relationship to what I am working on now in Brad’s lab. During my PhD, I identified a few phytochemicals from a plant that is native to Texas called ‘the snow on the prairie’. It gets its name from its green and white stripes. If you see this plant from a distance, it looks like it is covered in snow! Its scientific name is Euphorbia bicolor. I was working with the latex extract, which is a milky sap that is released when you cut different parts of Euphorbia bicolor. I found that latex extract from Euphorbia bicolor was able to alleviate pain hypersensitivity in rat models, both inflammatory and orofacial pain. I published a chapter in the textbook “Treatments, Mechanisms, and Adverse Reactions of Anesthetics and Analgesics” that summarizes my dissertation work. It has always been my interest to investigate alternative and complementary medicines to treat pain conditions that have better efficacy and less side effects.
Earlier this year, my sister, Dr. Arpita Basu, who is an Associate Professor at University of Nevada Las Vegas, got an invitation to publish with MDPI’s International Journal of Molecular Sciences. She forwarded it to me and asked if I had any papers or reviews that I would want to submit. At that time, I was working with Brad, so I said no. We knew that we were going to submit our primary research article to the Journal of Neuroscience. But I thought, “I can always write a review?”. That’s how it started. I decided to write a review on a well known plant-derived phytochemical called curcumin and its effects on neuropathic and postoperative pain conditions under preclinical and clinical settings. It was a collaborative project between my graduate mentor, Dr. Camelia Maier, a Professor at Texas Woman’s University, and my sister Dr. Arpita Basu, a clinical nutritionist. My sister’s research focuses on the health effects of dietary bioactive compounds for example tea, berries, cocoa, and how they can modulate disease biomarkers in type 2 diabetes, hypertension, and cardiovascular diseases. We kind of split the article up. Camelia and I focussed on the in vivo research, because that’s our forté, and my sister focussed on the clinical research. Then, we put it all together and worked on it as a whole and that’s how the final product came to be.
It sounds really fun to work on an article with your sister!
It was really fun. I think it is kind of an incentive or special encouragement because she’s not only my sister but also one of my collaborators! When I pursue my independent career in academia, I would always love to work with her because she does a lot of clinical studies. I could do the in vivo/in vitro work and she could do the clinical work. She recruits people for double blinded randomized control studies and gives all the dietary interventions. It’s also fun when you get to the point where your graduate mentors become your collaborators. When you’re a graduate student, you’re still in the process of training and they are still teaching you how to write. But now they give you feedback on your writing and they also provide valuable suggestions for moving your career forward. So yeah, it was so fun to work on this with them.
There’s a lot of literature out there on curcumin! What are your thoughts on “the powers” of curcumin in terms of adding it to our diets?
There are several clinical studies that have evaluated the protective effects of curcumin against many ailments, but mainly osteoarthritic pain, and these studies have given curcumin either as a supplement or incorporated into food. It is well known for its antioxidant, anti-inflammatory, and anti-mutagenic, and anti-microbial properties. There are also studies that use different curcumin formulations to increase the efficacy and bioavailability after ingestion. Curcumin is delivered as nano-particles, nano-vesicles, nano-capsules, emulsions, prodrugs, derivatives, and many other forms. In our review, we talked about the different curcumin formulations and their efficacy in alleviating neuropathic and postoperative pain both in vivo and in vitro. We mainly focused on rat and mouse models of neuropathic and postoperative pain models, and the rest of the article focused on the clinical effects. In India, we use turmeric. Turmeric has curcumin and we use it in curries. In the U.S., it is used in mustard sauce, cheese, and butter, as a preservative coloring agent. Curcumin is available in several forms including capsules, tablets, ointments, energy drinks, soaps, and cosmetics. The U.S. Food and Drug Administration (FDA) have approved curcumin as ‘generally recognized as safe’, or GRAS. It shows good tolerability and safe outcomes in clinical trials. So that’s why there are so many clinical trials employing curcumin in humans. Our review mainly focussed on the pain aspect. If you ask me, curcumin is definitely good, and coming from India, I know that in our day-to-day cooking we use curcumin and it has a lot of health benefits.
Do you think you’ll ever test curcumin on your molecular pathways?
I know, right? Maybe when I have my own lab. Biomedical science is so integrative, you can do so much intra- as well as inter-disciplinary research. Maybe that will be one of my goals, I will test the in vivo/in vitro models and my sister can test it in human patients… In that way, we can come under the big umbrella and work together! I will definitely focus on finding alternative therapeutics to treat or prevent different pain conditions.
There is a lot of interest in compounds like these and we are often trying to figure out what we want to supplement. Often a lot of the ‘nitty gritty’ research on these compounds is neglected and we are left to be the judge with correlative data. They might be really useful, so we need to test them in these controlled models! We could be putting people with chronic pain on really effective dietary interventions and supplements.
Yeah!
Do you have a fun science fact that you would like to share with us?
My dissertation project mainly involved this plant, Euphorbia bicolor. But at the same time, I also published some other papers where I looked at the effects of other plant extracts, such as Morus alba, Macular pomifera, and different berry extracts. I looked at their antioxidant, antiproliferative, antiestrogenic, and other biological properties. But if you ask me, I cannot identify a plant by looking at it! If you give me the extract, I can work on it, but I just cannot identify them by looking at the morphology. My PhD was a collaborative project between a plant lab and a pain biology lab, so Dr. Maier is a plant biochemist and would always make fun of me, like “You work with so many extracts, but if I held a Morus plant in front of you, you wouldn’t be able to identify it!” and I would reply, “Nope! If you give me the extract or the labelled plant, I’m going to make extracts, do the purification, and work on it, but I cannot identify them!”. Dr. Maier was really good at it, she used to take me to the field in Denton, Texas to identify different plant species… but I had no idea. I can tell that I’m not a good plant taxonomist!
That’s so funny! And it shows how focussed we can be as researchers; we can know absolutely everything about an extract but not how to spot the plant in the wild!
Working in research can be pretty stressful at times. Do you have any tips for staying happy and balanced as a neuroscientist?
It is extremely stressful! I would suggest taking at least 30 minutes off every day from your busy schedule to do something that makes your soul happy. It can be an indoor or an outdoor activity. To rejuvenate myself, I do yoga and practice meditation everyday. I love to do that while inhaling the fragrance of natural incense. I’m not a religious person, I am more of a spiritual person. I believe that there is a superpower. I don’t define that ‘power’ as ‘he’ or ‘she’. But spirituality is important for your body and your mind. If you are having a difficult time, or you don’t know which path to choose, I believe that if you pray to that ‘power’ from the core of your heart, your prayers will be answered and you will be shown the right path.
What are your thoughts on academic research work culture in the U.S.A.?
The first word that comes to my mind is 'productivity'. After coming from India to pursue my doctoral studies in the U.S., I saw this nation as a melting pot of different values, beliefs, cultures, and traditions. Academic research in the U.S. provides equal opportunities and success for all individuals to perform research, publish in top tier journals, get external and internal funding, as well as present your findings to the scientific community worldwide. Equal opportunity. That is my take on the academic research career. It has a lot of opportunities but you have to find what best suits you. My favourite thing about the U.S. is that there are so many people coming from so many cultures and we are all exchanging ideas. In this kind of work culture, the more ideas you incorporate, the more fruitful the outcome. I think this is why the U.S. academic system is flourishing.
What would be your advice to a junior student wanting to pursue research in your field?
If you love research, pursue it. It takes a long time, and requires a lot of patience, hard work, and openness to criticism. Even when you give a small draft to your P.I., you will get criticism. I’m learning every day from my lab’s research technician, my colleagues, other professors, my P.I., my graduate school mentors, my sister, my mom… Every single day is a learning process. I believe and I have experienced that nothing will come overnight. It takes time. Sometimes we do research where the outcomes aren’t significant enough to publish, so you have to take it all with a grain of salt. Sometimes things don’t work out well. You reach a dead end, or the results don’t make sense. You might realize that you can’t move forward with a project. When you start your Ph.D. work, you need to find something that’s new, but at the same time you have these timelines to graduate and move on to the next step. Do research only if you really love it, otherwise it will be a drag.
Do you enjoy living and working in Pittsburgh? It’s a pretty cool town!
I love Pittsburgh. I am really fascinated by the bridges, there are 25 of them. They are a really special feature, unlike any other city. I really enjoy this hilly town after coming from Texas, it looks so beautiful. The Mount Washington neighborhood is my go-to place, you get to see the lovely Pittsburgh from above and there are some very nice restaurants. It’s nice to take pictures there at sunset or at night.
How do you hope to see the scientific landscape change for women-identifying scientists going forward, especially within your field?
I again want to stress on equal opportunity. I think there should be no discrimination. The innovation and competitiveness of a workplace can be enhanced by employing women of different ethnicities, socioeconomic status, and backgrounds. The more diverse the team, the more creative the results. It will outperform the homogenous team every time. I hope to see more women entering the field of neuroscience and especially pain neurobiology, and I hope to see their work and accomplishments celebrated. I look forward to that. As an immigrant, this country has given me a lot of opportunities. However, there are some caveats. For example, as an immigrant, we cannot apply for many grants and fellowships. But, every coin has two sides and the pros far outweigh the cons in terms of the opportunities this country provides. I’m excited about those opportunities and can’t wait to see more women enhancing this field.
Do you have anything else you would like to add?
I would like to thank you for this opportunity! You’re doing an incredible job of highlighting the publications and the stories behind the publication from scientists across different disciplines. I am honored to receive the Society for Neuroscience’s (SfN’s) “Trainee Professional Development Award” to present my postdoc research at SfN’s 50th Annual meeting. I would also like to thank my co-mentor Dr. Dayna Averitt who first introduced me to this pain field! One day, we finished our journal club and were having a little chat outside her office. At the time I was working on Euphorbia bicolor with Dr. Camelia Maier and was telling her about this plant. It was, again, kind of that striking moment. She said that she was writing a manuscript on resiniferatoxin, a plant compound isolated from the plant Euphorbia resinifera. That’s how I got started talking, and boom, that was the turning point of my dissertation project. We decided that we were going to initiate an interdisciplinary collaboration where we brought together plant biochemistry and pain neurobiology. You never know when that moment will strike up and change your research direction. I’d also like to thank Dr. Taylor, my postdoc mentor. I’m incredibly thankful to him for his continuous support, guidance, and encouragement. Last but not least, my sister Arpita Basu, and my parents. Without their unconditional love and support I wouldn’t be here enjoying everything research has to offer!
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