Interaction of Morphine and Selective Serotonin Receptor Inhibitors in Rats Experiencing Inflammatory Pain

Abstract

Citalopram and paroxetine are selective serotonin reuptake inhibitors and also have antinociceptive effects. We investigated the antiallodynic and antihyperalgesic effects of intrathecally administered morphine, citalopram, paroxetine, and combinations thereof, in a rat model in which peripheral inflammation was induced by complete Freund's adjuvant (CFA). Drugs were intrathecally administered via direct lumbar puncture. Mechanical allodynia was measured using a Dynamic Plantar Aesthesiometer. Thermal hyperalgesia and cold allodynia were determined by measuring latency of paw withdrawal in response to radiant heat and cold water. Behavioral tests were run before and 15, 30, 45, and 60 min after intrathecal injection. Intraplantar injection of CFA produced mechanical allodynia, thermal hyperalgesia, and cold allodynia. Intrathecally administered morphine (0.3 or 1 μg) had antiallodynic or antihyperalgesic effects (24.0%-71.9% elevation). The effects of morphine were significantly increased when a combination of citalopram (100 μg) and paroxetine (100 μg) was added (35.2%-95.1% elevation). This rise was reversed by naloxone and methysergide. The effects of citalopram and paroxetine were also reversed by naloxone and methysergide. We suggest that the mu opioid receptor and serotonin receptors play major roles in production of the antiallodynic and antihyperalgesic effects of morphine, citalopram, paroxetine, and combinations thereof, in animals experiencing inflammatory pain.

Paroxetine Increases δ Opioid Responsiveness in Sensory Neurons

“…The catalyst that restores functional opioid receptor competence depends on the induction of a signaling cascade that results in the summation of GRK2 sequestration from the receptor (Brackley et al, 2016). FDA-approved drug paroxetine, which binds and inhibits GRK2 (Thal et al, 2012), may have analgesic potential by enhancing peripheral opioid receptor competence in multiple pain modalities (Lee et al, 2012). In this study, we identify a GRK2-dependent mechanism that establishes a rationale for clinical trial implementation of repurposing of the FDA-approved drug paroxetine as a potential co-treatment to restore peripheral opioid competence.…”

“…In mice, paroxetine dose-dependently enhances endogenous opioid antinociception (Gray et al, 1998;Kesim et al, 2005), mediated by DOR (Gray et al, 1998). In rats, paroxetine enhances antinociception produced by systemicallyadministered low dose morphine, presumably targeting peripheral opioid receptors, in multiple pain modalities including neuropathic, mechanical, thermal, and cold allodynia (Lee et al, 2012). However, the mechanism that underlies paroxetine priming of opioid receptor analgesic competence has yet to be explored.…”

“…Given that paroxetine enhances opioid analgesia (Lee et al, 2012) and directly inhibits GRK2 (Thal et al, 2012), which constitutively maintains peripheral DOR incompetence (Brackley et al, 2016;Brackley et al, 2017), we hypothesized that paroxetine-induced DOR competence in the periphery is mediated by sequestration of GRK2. This proof-of-concept study in male rats uses a drug recycling approach to target protein-protein interactions that govern peripheral opioid receptor responsiveness in the absence of inflammation.…”

Minimally invasive technique for intrathecal administration of morphine in rats: practicality and antinociceptive properties

“…This dose is comparable to the highest doses used by Yaksh, 22,23 and is substantially higher than doses used in recent fundamental studies. 36,43 The injected volume (i.e. 0.05 mL per rat) may have varied slightly between animals due to the simple apparatus used (disposable hypodermic needles and syringes), but sits within the commonly quoted range.…”

Διερεύνηση Των Παραγόντων Φλεγμονώδους Αντίδρασης Του Επισκληρίδιου Καθετήρα Κατά Την Επισκληρίδια Αναισθησία Και Αναλγησία

“…αναλγητική δράση των οπιοειδών έχει μελετηθεί διεξοδικά στην αντιμετώπιση του οξέος και του χρόνιου πόνου. Οι παράγοντες της φλεγμονώδης αντίδρασης ελαττώνονται και η απάντηση στο χειρουργικό stress είναι μειωμένη 84…”