Biology subjects

Jutkiewicz, E. M.

Publications and source records attributed to Jutkiewicz, E. M..

4 recordsLinked to original sources

bioRxiv2025

Delta Opioid Receptors on Parvalbumin Neurons are Necessary for the Convulsant and Anxiolytic Effects of the Delta Agonist SNC80

The delta opioid receptor (DOR) is expressed broadly throughout the central and peripheral nervous systems. Activation of DOR by exogenous and endogenous ligands regulates pain, motivation, emotion and memory, but the cells and neural circuits mediating these behavioral effects remain poorly characterized. Parvalbumin-expressing (PV) interneurons express high levels of DOR transcript (OPRD1) and protein (Birdsong et al 2019). Parvalbumin (PV) interneurons also play a role in pain and emotional processing, suggesting that DOR signaling on PV interneurons may modulate these behaviors. To address this question we used a conditional knockout mouse line (Floxed DOR; PV-cre) to delete DOR from PV-expressing cells. First, we validated the functional loss of DOR through whole-cell electrophysiology experiments. Next, we characterized baseline behavioral phenotypes and the convulsant, pro-locomotive and anxiolytic-like behavioral responses induced by the DOR agonist SNC80 in Floxed DOR; PV-Cre mice and their littermate controls. Interestingly, we found that the convulsant and anxiolytic effects of the DOR agonist SNC80 were diminished in Floxed DOR;PV Cre animals. However, baseline behavioral phenotypes, SNC80-induced spontaneous hyperlocomotion and respiratory stimulation were conserved. These novel findings indicate that the pro-convulsant and anxiolytic effects of DOR agonists are anatomically separable from the locomotor stimulating effects and are dependent on DOR expression on PV interneurons.

neuroscience↗

bioRxiv2025

The effects of chronic neuropathic pain states on MOR-agonist induced antihyperalgesic-like effects and rate suppressant effects

Chronic neuropathic pain affects 6.9-10% of the U.S. population. While mu opioid receptor (MOR) agonists are not first-line treatments for chronic pain, previous data suggests that [~]70% of chronic neuropathic pain patients receive MOR agonist treatment. Previous studies demonstrated decreased MOR expression and activity in pain states compared with non-injured or sham controls; however, we know little about how chronic pain states may alter the antinociceptive- and antihyperalgesic-like effects of MOR agonists in vivo. Therefore, the goal of this study was to determine if there were significant differences in MOR agonist-induced antinociceptive- or antihyperalgesic-like effects between SNI and sham groups. MOR agonist-induced antinociceptive- and antihyperalgesic-like effects were evaluated in SNI and sham groups repeatedly over 6 months. MOR agonists induced dose-dependent antinociceptive- and antihyperalgesic-like effects in male and female rats in the expected rank order of potency (fentanyl>morphine[≥]nalbuphine). Over time, there were small rightward shifts in fentanyl- and morphine-induced effects; however, these rightward shifts were observed in sham and SNI groups, suggesting this occurred independent of pain state. Interestingly, in sham and SNI groups, nalbuphine-induced effects were more potent 6 months post-operatively than 3 months, suggesting the potency of nalbuphine changed over time, independent of pain state. Other, non-MOR agonist analgesics were evaluated. Collectively, these data indicate that SNI failed to alter MOR agonist-induced antinociceptive- and antihyperalgesic-like effects. Future studies should evaluate if the SNI-independent increase in sensitivity to nalbuphine is related to the partial KOR agonist activity and if SNI-induced hypersensitivity alters tolerance following repeated administration of MOR agonists. Significance StatementMany chronic pain patients are treated with opioids, but we understand relatively little about how chronic pain may alter the in vivo effects of opioid analgesics. This study demonstrates that, compared to sham groups, SNI-induced hypersensitivity did not alter the potency or efficacy of opioid analgesics, opioid-induced tolerance to analgesic-like effects, or opioid-induced rate suppressant effects in either male or female rats.

pharmacology and toxicology↗

bioRxiv2024

The effects of chronic neuropathic pain states on the discriminative stimulus effect of fentanyl and other MOR agonists

Pleasant subjective effects of drugs (e.g., euphoria) have been demonstrated to contribute to their abuse potential. In humans, there is some evidence that acute pain states may decrease the positive subjective effects of opioids; however, no studies have directly tested the impact of a long-lasting pain state. Therefore, the goal of this study was to directly evaluate the discriminative stimulus of mu opioid receptor (MOR) agonist, fentanyl, or the non-opioid drug of abuse, cocaine, in the presence or absence of spared nerve injury (SNI) induced chronic neuropathic pain. Prior to surgery, MOR agonists (fentanyl, morphine, nalbuphine) dose-dependently increased % fentanyl-like responding, as expected; surprisingly, after surgery, we saw small, significant rightward shifts in the fentanyl and morphine dose response curves in both sham and SNI groups suggesting that the observed shifts were not due to chronic pain. In both sham and SNI groups, there was an increase in the generalization of nalbuphine to the fentanyl-discriminative stimulus. There was no change in the discriminative stimulus of cocaine (or amphetamine substitutions) over 4 months of SNI-induced chronic neuropathic pain or sham states, suggesting that the SNI model failed to alter the discriminative stimuli of fentanyl and cocaine. Following induction of chronic neuropathic pain, there was an observed increase in quinpirole-induced generalization to the cocaine discriminative stimulus. In the future, studies should directly examine the abuse potential of low efficacy MOR agonists and dopaminergic agonists in the presence and absence of chronic pain states. Significance StatementSubjective or interoceptive effects of drugs of abuse are known to contribute to the abuse potential. This study demonstrated that long-lasting neuropathic pain failed to alter the discriminative stimulus of mu opioid receptor agonists or cocaine; however, we observed an increase in quinpirole-induced generalization to the cocaine discriminative stimulus, suggesting the abuse potential of direct dopaminergic agonists should be further evaluated in the presence or absence of pain states.

pharmacology and toxicology↗

bioRxiv2024

The effects of chronic neuropathic pain on the self-administration of highly potent MOR agonist, fentanyl

There is significant overlap between chronic pain and opioid use disorder (OUD) patient populations such that approximately 50-65% of chronic pain patients have OUD. However, we understand relatively little about how chronic, long-lasting pain states alter ongoing self-administration of opioid analgesics. Thus, the goal of this study was to determine if chronic neuropathic pain altered the ongoing self-administration of fentanyl, or a non-opioid drug of abuse, cocaine. Animals were trained to self-administer fentanyl or cocaine in a multi-dose self-administration procedure composed of five 25-min components, exposing animals to multiple doses of drug per day. Operant behavior was established prior to induction of chronic pain via the spared nerve injury (SNI). Animals were allowed 72 hours of post-operative recovery and resumed self-administration on post-operative day 4. All animals dose-dependently self-administered fentanyl prior to surgery. On post-operative day 4, both sham and SNI groups showed a significant decrease in fentanyl self-administration. By post-operative day 9, fentanyl intake was no longer significantly different from pre-surgical intake. Over the course of 4 weeks of self-administration, there was an increase in intake of specifically the 10 ug/kg/inf dose of fentanyl. Cocaine self-administration was not altered at any point following either surgery. Collectively, these results suggest that SNI-induced hypersensitivity failed to alter the reinforcing effects of fentanyl, or non-opioid drug of abuse, cocaine. Future studies should evaluate the abuse potential of lower efficacy MOR agonists such as nalbuphine or buprenorphine, as small changes were observed in fentanyl-maintained behavior over time in both SNI and sham groups. Significance statementMOR agonists are excellent analgesics; however, they are not first-line treatments for chronic pain, in part due to abuse potential. This study demonstrates that small, significant rightward shifts in the fentanyl dose response curve were observed following induction of both sham and spared nerve injury (SNI) (chronic neuropathic pain-like) states, suggesting these changes were observed independent of pain state. These data indicate that SNI-induced neuropathic pain failed to alter the ongoing self-administration of highly potent MOR agonist, fentanyl.

pharmacology and toxicology↗