Stress-opioid interactions: a comparison of morphine and methadone

Abstract

Abstract:The utility of methadone and morphine for analgesia and of methadone for substitution therapy for heroin addiction is a consequence of these drugs acting as opioid receptor agonists. We compared the cataleptogenic and antinociceptive effects of single subcutaneous doses of methadone hydrochloride (1-4 mg/kg) and morphine sulfate (2.5-10 mg/kg) using catalepsy and hot-plate tests, and examined the effects of the highest doses of the drugs on Fos protein expression in selected brain regions in male Sprague-Dawley rats. Methadone had greater cataleptogenic and analgesic potency than morphine. Fos immunohistochemistry revealed substantial effects on the Fos response of both the stress induced by the experimental procedures and of the drug exposure itself. There were three response patterns identified: 1) drug exposure, but not stress, significantly elevated Fos-positive cell counts in the caudate-putamen; 2) stress alone and stress combined with drug exposure similarly elevated Fos-positive cell counts in the nucleus accumbens and cingulate cortex; and 3) methadone and morphine (to a lesser extent) counteracted the stimulatory effect of nonpharmacological stressors on Fos protein expression in the somatosensory cortex barrel field, and Fos-positive cell counts in this region correlated negatively with both the duration of catalepsy and the latency time in the hot-plate test. The overlap between brain regions reacting to nonpharmacological stressors and those responding to exogenous opioids suggests that stress contributes to opioid-induced neuronal activation.

Pharmacokinetics and pharmacodynamics of cyclopropylfentanyl in male rats

“…By using a behavior scoring method based on immobility, flattened body posture, and splayed limbs, we demonstrate that cyclopropylfentanyl produces catalepsy-like effects at 100 and 300 µg/kg doses, lasting up to 4 h after the higher dose. The ED 50 for cyclopropylfentanyl to induce catalepsy was right shifted when compared to that of analgesia (i.e., 87 µg/kg), which agrees with the findings from previous studies reporting that higher morphine doses are needed to induce cataleptic effects compared to analgesic effects (Pöyhiä and Kalso 1992 ; Taracha et al 2009 ). We also show that cyclopropylfentanyl induces hypothermia at the highest dose administered (300 μg/kg), with temperatures decreasing in a manner similar to the effects of other synthetic opioids such as carfentanil and U-47700 (Bergh et al 2019a ; Truver et al 2020 ).…”

Development of sensitization to methamphetamine in offspring prenatally exposed to morphine, methadone and buprenorphine

“…; Taracha et al . ). Most recently, a study showed a negative genetic correlation between METH consumption and sensitivity to the opioid‐induced effects in the selectively bred mouse lines with different level of METH intake (Eastwood & Phillips ).…”

Effects of μ-Opioid Receptor Agonists in Assays of Acute Pain-Stimulated and Pain-Depressed Behavior in Male Rats: Role of μ-Agonist Efficacy and Noxious Stimulus Intensity

“…assays of acid-stimulated stretching in rats and mice (Cowan et al, 1977;Fürst, 1991;Stevenson et al, 2006;Pereira Do Carmo et al, 2009). Previous studies have also shown that m-opioid agonists block other examples of pain-stimulated behavior, such as tail-or paw-withdrawal responses from noxious thermal stimuli Holtzman, 1991, 1992;Gringauz et al, 2001;Taracha et al, 2009) or withdrawal responses in subjects rendered hypersensitive to thermal or mechanical stimuli by inflammatory or neuropathic manipulations (Wang et al, 2006;Cobos et al, 2012;Jagla et al, 2014). m-Agonist effects on pain-stimulated behaviors are often interpreted as evidence consistent with clinical analgesic efficacy .…”