Inhibition of fatty acid amide hydrolase in the CNS prevents and reverses morphine tolerance in male and female mice

Abstract

Background and Purpose: Fatty acid amide hydrolase (FAAH) is an intracellular serine amidase that terminates the signalling of various lipid messengers involved in pain regulation, including anandamide and palmitoylethanolamide. Here, we investigated the effects of pharmacological or genetic FAAH removal on tolerance to the antinociceptive effects of morphine. Experimental Approach: We induced tolerance in male and female mice by administering twice-daily morphine for 7 days while monitoring nociceptive thresholds by the tail immersion test. The globally active FAAH inhibitor URB597 (1 and 3 mgÁkg −1 , i.p.) or the peripherally restricted FAAH inhibitor URB937 (3 mgÁkg −1 , i.p.) were administered daily 30 min prior to morphine, alone or in combination with the cannabinoid CB 1 receptor antagonist AM251 (3 mgÁkg −1 , i.p.), the CB 2 receptor antagonist AM630 (3 mgÁkg −1 , i.p.), or the PPAR-α antagonist GW6471 (4 mgÁkg −1 , i.p.). Spinal levels of FAAH-regulated lipids were quantified by LC/MS-MS. Gene transcription was assessed by RT-qPCR. Key Results: URB597 prevented and reversed morphine tolerance in both male and female mice. This effect was mimicked by genetic FAAH deletion, but not by URB937. Treatment with AM630 suppressed, whereas treatment with AM251 or GW6471, attenuated the effects of URB597. Anandamide mobilization was enhanced in the spinal cord of morphine-tolerant mice. mRNA levels of the anandamide-producing enzyme N-acyl-phosphatidylethanolamine PLD (NAPE-PLD) and the palmitoylethanolamide receptor PPAR-α, but not those for CB 2 , CB 1 receptors or FAAH, were elevated in spinal cord Conclusion and Implications: FAAH-regulated lipid signalling in the CNS modulated opiate tolerance, suggesting FAAH as a potential target for opiate-sparing medications.

Positive Allosteric Modulation of CB1 Cannabinoid Receptor Signaling Enhances Morphine Antinociception and Attenuates Morphine Tolerance Without Enhancing Morphine- Induced Dependence or Reward

“…Cannabinoid and opioid systems interact to modulate tail-flick antinociception (Scavone and Van Bockstaele, 2009). Tolerance prevention (Cichewicz and Welch, 2003;Fotio et al, 2020) as well as cross-tolerance between exogenous cannabinoid agonists and morphine have been reported in non-human primates (Gerak et al, 2015) and rats (Altun et al, 2015a,b). In otherwise naïve rats, intra-PAG injection of the cannabinoid receptor agonist HU-210 enhanced morphineinduced antinociception and prevented morphine tolerance in the tail-flick test (Wilson et al, 2008).…”

N-Oleoylglycine and N-Oleoylalanine Do Not Modify Tolerance to Nociception, Hyperthermia, and Suppression of Activity Produced by Morphine

“…Chronic dosing of morphine (twice daily 20 mg/kg, except day 1, for 13 days) resulted in tolerance to the hypolocomotor and the anti-nociceptive, but not to the hyperthermic, effects of morphine, as has been reported to the anti-nociceptive effects of morphine by Fotio et al (2020). Here rats were injected with OlGly (5 mg/kg, ip, Experiment 1) or OlAla (5 mg/kg ip, Experiment 2) prior to each chronic treatment with morphine or saline to determine if these fatty acid amides that act in vitro as FAAH inhibitors and PPARα agonists (Donvito et al, 2019;Ayoub et al, 2020), would interfere with morphine tolerance as has been reported for the FAAH inhibitor, URB597 (Fotio et al, 2020). However, at least at a dose of 5 mg/kg, ip, neither OlGly nor OlAla administration interfered with the establishment of tolerance to the anti-nocicieptive and the hypolocomotor effects of morphine.…”

“…Unlike OlGly and OlAla, the FAAH inhibitor URB597, has recently been shown to prevent tolerance to morphine antinociception in the tail flick test using a similar procedure and dosing schedule as was used here (Fotio et al, 2020). The effect of URB597 on morphine tolerance was reversed by pretreatment with a cannabinoid 2 (CB 2 ) receptor antagonist (AM630) and partially suppressed by pretreatment with a FIGURE 2 | OlAla (A) the mean (± sem) distance (cm) traveled in the locomotion test, (B) the mean (± sem) latency to tail flick from a hot water bath, (C) mean (± sem) body temperature ( • F), displayed by the various groups across the 13 days of chronic morphine.…”

“…If OlGly and OlAla are effective in the treatment of MWD, it is important to determine if they might also modify tolerance to morphine at the most effective therapeutic dose of 5 mg/kg, ip, when tested under similar housing conditions as our previous work. Indeed, recent evidence indicates that the FAAH inhibitor, URB597, prevents tolerance to morphine nociception in the tail immersion test ( Fotio et al, 2020 ). Here we evaluated the potential of OlGly and OlAla to modify tolerance to nociception, hyperthermia, and suppression of activity produced by morphine under a similar morphine treatment regime as employed by Fotio et al (2020) .…”

Nalbuphine ameliorates morphine/tramadol-induced dependence and tolerance to analgesia through locus coereulus (LC) norepinephrine

“…However, repeated administration of morphine for 15 days was associated with tolerance to its analgesic activity as evidenced by the significant decrease in the latency time observed at day 15 of morphine administration compared to its effect on day 1. The development of tolerance following repeated morphine administration was previously reported (Fotio, Palese et al 2020).…”