I am very pleased that NIDA has decided* to fund our R01 application which proposed investigating the impact of oxycodone, heroin and fentanyl in middle aged rats. Our Explicating Vulnerability and Resilience in Opioid Self-Administration in Middle Aged Rats project will run from 9/15/2024 to 6/30/2029.
As outlined in a prior post, the opioid crisis which developed over the past two decades included a steeper rise in overdose fatality for 45-65 year olds compared with other age groups. Given the vast diversity of prior drug history, reason for using opioids, the specific opioids used and accumulating health problems of middle aged humans, this brings up multiple possible reasons. Some of these can be best addressed in animal models, given the ability to control many variables and explicitly test hypotheses. We can explicitly control prior exposure to drugs, either opioids or other. We can control when in a lifespan the exposure to opioids occurs. We can control dose and frequency and the route of exposure.
Our scientific orientation in my laboratory leads us to a focus on the rewarding properties of opioids and there are many questions about whether opioid drugs are more or less likely to lead to compulsive seeking behavior in middle age, compared to younger adults.
This led to my proposing the new studies which have been selected for funding.
It’s a pretty simple project, to be quite honest. This simplicity reflects the poor state of knowledge on the topic at present. There are only very limited studies of anything to do with the rewarding effects of opioids in rats past the younger adult age published, and only one of these is a study of (morphine) self-administration. This latter was conducted in very aged rats, near their natural lifespan of ~ 24 months. A study of the impact of morphine on intra-cranial self-stimulation reward was conducted at 24 months of age…but in a Fisher 344 / Brown Norway F1 cross that lives much longer than most rats. Suffice it to say that there is very little evidence on the impact of opioids (particularly considering the ones that are most pertinent to the non-medical use problem, i.e., oxycodone, heroin and fentanyl) in middle aged rats.
There is no point, in my view, of proposing elaborate studies involving post-mortem assessment of brain alterations before and unless we determine that the responses of middle aged rats to opioids are different. Maybe aging has nothing to do with the changes in overdose rate?
So we opted to propose some initial, foundational work.
Our proposed Specific Aims are as follows.
Specific Aim I: To determine if the acute effects of opioids differ in middle-aged adult rats.
We first had to come up with a target age for the “middle aged” designation that would put us somewhere reasonably near the human 50-65 year old population that motivated this work. We settled on 12 months for a number of reasons including that it’s halfway through the natural lifespan and female rats stop cycling around this age. So we will be contrasting young adult (3 month old) and middle aged (12 month old) rats throughout this study. Investigations under this first Aim will simply determine if locomotor stimulant, anti-nociceptive, thermoregulatory, respiratory suppressive and brain-reward altering effects of oxycodone, heroin and fentanyl differ between young adult and middle age rats.
Specific Aim II: To determine if intravenous self-administration of opioids differs between
young adult and middle-aged rats.
The second Aim will determine if the intravenous self-administration of opioids differs between young adult and middle aged rats. This is really our core interest in this topic, and the other studies are in some senses going to be support for these investigations. The first Aim’s studies will feed into these studies by determining suitable drug doses to enhance our inference about increased, decreased or unchanged propensity to self-administer in middle adulthood. The Aim III studies will help to tell us whether the intravenous route of self-administration produces results that generalize to other routes of administration.
Specific Aim III: To determine if inhalation or oral routes of administration differentially alter
opioid seeking in young adult versus middle-aged rats.
The third Aim will determine if the oral route for oxycodone administration or the inhalation route for heroin self-administration. We proposed intravenous route in Aim II because it is a model that is very well-established in the field and we have a lot of experience with it in my lab, including as it is applied to opioid drug seeking behavior in rats. Nevertheless, the most obvious starting point for later-life initiation of non-medical opioid use in humans is via oral medications such as oxycodone. A transition to heroin can occur but many individuals do not switch to intravenous use, preferring to either insufflate or inhale heroin vapors (“chasing the dragon”). This latter method, btw, is a long tradition with opioids- opium “smoking” was actually done by heating the material to vaporization, not by combusting it.
Our pursuit of this funding was originally encouraged by a Notice of Special Interest (NOT-DA-20-014) issued by NIDA in 2020. The research priorities that are mentioned are extensive and very much meet anyone’s initial questions upon contemplating this health issue. The NOSI expired in September of 2023, just months before I prepared the revised version of the proposal, and no similar NOSI or other FOA have appeared as far as I’ve noticed. There do not appear to be a large number of studies related to this funded by NIDA. No matter. I don’t know why they lost interest but at least we will be able to address some of these questions.
*As noted in the prior post, the study section returned a 26 impact score, at 10.0 %ile which was not certain to fund. We had to wait for the last regular batch of awards (i.e., on 9/15) for Cycle III awards which have a 7/1 first possible starting date.
For those interested in process, we ended up with a 10% reduction to the proposed budget. This is not uncommon when the NIH is operating under a Continuing Resolution or has been doing so for much of the year. It can also happen under normal circumstances. My proposal is one of the now exceedingly rare R01 proposed within the modular budget limit (no more than $250,000 per year in direct costs) and so it is a little annoying they cut this small of a project. While 10% may not sound like much, it is roughly the amount of one of the Personnel lines proposed in the Budget Justification.
TL neuro 