Biology subjects

Traynor, J. R.

Publications and source records attributed to Traynor, J. R..

7 recordsLinked to original sources

bioRxiv2026

Effects of the Mu Opioid Receptor Positive Allosteric Modulator BMS-986122 On Opioid Efficacy in Rat Neuropathic Pain States

BackgroundNeuropathic pain is a major source of disability and distress with few pharmacological options for treatment. Opioid drugs can be effective, but high doses are needed, leading to unwanted effects. BMS-986122 is a positive allosteric modulator of the mu opioid receptor that potentiates acute opioid antinociception without increasing opioid-induced constipation, reward, or respiratory depression. Therefore, we asked if BMS-986122 could increase the effects of low-dose opioid analgesics in chronic neuropathic pain. MethodsWe employed the spared nerve injury and tibial neuroma models in rats and assessed the tactile hypersensitivity of the hind paw and site of neuroma, respectively. ResultsAdministration of low doses of (R)-methadone, morphine, or buprenorphine slightly reduced the tactile hypersensitivity of the hind paw the in spared nerve injury model. Pretreatment with BMS-986122 significantly enhanced the reversal of hypersensitivity, reaching the effect of high-dose gabapentin, a standard of care in neuropathic pain. Pretreatment with BMS-986122 similarly increased the anti-allodynic effects of low dose (R)-methadone on neuroma pain. A similar effect of (R)-methadone in the absence of BMS-986122 was only observed at a dose where respiratory distress was seen. ConclusionsThese findings show that allosteric modulators of the mu opioid receptor such as BMS-986122 can enhance opioid activity that could translate to a safe and effective treatment for chronic neuropathic pain.

pharmacology and toxicology↗

bioRxiv2026

Discovery and dynamic pharmacology of μ-opioid receptor positive allosteric modulators

Opioid agonists such as morphine and fentanyl exert analgesic effects by binding and activating the {micro}-opioid receptor ({micro}OR), yet agonism of the {micro}OR causes a slate of serious side effects. {micro}OR-mediated addiction and respiratory depression are the major causes of the current opioid overdose crisis, largely driven by the explosion in illicit use of fentanyl, a potent opioid receptor full agonist. Given these serious side effects (and high resulting societal cost), molecules that act as analgesics with distinct mechanisms of action are of great interest. Positive allosteric modulators (PAMs) of the {micro}OR have the potential to avoid many off-target side effects of conventional opioid orthosteric agonists by enhancing the signaling properties of natural opioid peptide systems. We used a DNA-encoded chemical library screening approach to selectively discover active-state-specific {micro}OR PAMs. Two out of 3 selected prospective PAMs displayed the anticipated enhancement in agonist activity. The most effective of these compounds enhanced the activity of all orthosteric opioid agonists tested, including the native opioid peptide met-enkephalin. Little is known about the underlying dynamic basis of allosteric modulation of Family A GPCRs like the {micro}OR. To that end, we used single-molecule fluorescence resonance energy transfer experiments to detail the impact that our novel {micro}OR PAM has on the dynamic activation behavior of a key region on the intracellular face of the receptor. Our results here provide both a new chemical scaffold that acts as a {micro}OR PAM and detailed pharmacological and dynamic insights into its mechanism of action.

biophysics↗

bioRxiv2025

μ-Opioid Receptor Superagonists Engage a Sodium-Bound Active State

The simple two-state conformational selection model of G-protein coupled receptor (GPCR) activation suggests that, by binding to a high affinity site, an agonist will shift receptor equilibrium in favor of active state (R*) conformations that recruit heterotrimeric G proteins over inactive state (R) conformations. Agonist binding to the -opioid receptor is highly sensitive to Na+ ions which stabilize an inactive receptor state. Higher efficacy opioid agonists, such as DAMGO and fentanyl, are sensitive to Na+ compared to lower efficacy ligands at the -opioid receptor. However, the binding of the highly potent oripavine agonists etorphine and dihydroetorphine are less sensitive to Na+ than expected such that the prevailing models fail to explain their pharmacology. To explain this discrepancy, experiments were performed to evaluate the binding properties and G protein activation of the highly potent agonists carfentanil, BU72, etorphine, etonitazene and similarly potent opioid peptidomimetics in comparison to the standard agonists DAMGO, fentanyl, and morphine in the presence or absence of Na+ or K+ ions. Several of the superagonists retained high affinity and potency in both ionic conditions, whereas DAMGO, fentanyl and morphine displayed enhanced binding and signaling in K+, compared to Na+ ions. These functional parameters were used to determine an intrinsic efficacy value, determined as [Formula]. Comparison of affinity shifts with intrinsic efficacy afforded a negative correlation in which superagonists with the highest intrinsic efficacy are least sensitive to Na+. These data suggest that select -opioid receptor superagonists have high affinity for the Na+ bound receptor states (R) and shift these species into active receptor conformations (R*) that efficiently couple to G proteins. Significance StatementThe simple theory of conformational selection suggests the binding affinities of high efficacy -opioid receptor ligands, such as fentanyl and DAMGO, are more sensitive to Na+ and guanine nucleotide which stabilize inactive receptor states than lower efficacy agonists and antagonists. Here, we show that ligands with high intrinsic efficacy (superagonists) are much less sensitive to Na+ and guanine nucleotide. This work demonstrates that highly potent ligands can engage a low affinity Na+-bound receptor state that may then convert to a receptor species that efficiently couples to G protein - i.e. a conformational induction.

pharmacology and toxicology↗

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↗

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↗

bioRxiv2024

Xylazine Exacerbates Fentanyl-Induced Respiratory Depression and Bradycardia

Fatal opioid overdoses in the United States have nearly tripled during the past decade, with greater than 92% involving a synthetic opioid like fentanyl. Fentanyl potently activates the -opioid receptor to induce both analgesia and respiratory depression. The danger of illicit fentanyl has recently been exacerbated by adulteration with xylazine, an 2-adrenergic receptor agonist typically used as a veterinary anesthetic. In 2023, over a 1,000% increase in xylazine-positive overdoses was reported in some regions of the U.S. Xylazine has been shown to potentiate the lethality of fentanyl in mice, yet a mechanistic underpinning for this effect has not been defined. Herein, we evaluate fentanyl, xylazine, and their combination in whole-body plethysmography (to measure respiration) and pulse oximetry (to measure blood oxygen saturation and heart rate) in male and female CD-1 mice. We show that xylazine decreases breathing rate more than fentanyl by increasing the expiration time. In contrast, fentanyl primarily reduces breathing by inhibiting inspiration, and xylazine exacerbates these effects. Fentanyl but not xylazine decreased blood oxygen saturation, and when combined, xylazine did not change the maximum level of fentanyl-induced hypoxia. Xylazine also reduced heart rate more than fentanyl. Finally, loss in blood oxygen saturation correlated with the frequency of fentanyl-induced apneas, but not breathing rate. Together, these findings provide insight into how the addition of xylazine to illicit fentanyl may increase the risk of overdose. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=114 SRC="FIGDIR/small/608310v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@1a3aabeorg.highwire.dtl.DTLVardef@1eac11org.highwire.dtl.DTLVardef@1b2ceb9org.highwire.dtl.DTLVardef@220f06_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗