PMID- 35794162
OWN - NLM
STAT- MEDLINE
DCOM- 20220708
LR  - 20220913
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 12
IP  - 1
DP  - 2022 Jul 6
TI  - REL-1017 (esmethadone; D-methadone) does not cause reinforcing effect, physical 
      dependence and withdrawal signs in Sprague Dawley rats.
PG  - 11389
LID - 10.1038/s41598-022-15055-3 [doi]
LID - 11389
AB  - REL-1017 (esmethadone, D-methadone) is the opioid-inactive d-isomer of racemic 
      D,L-methadone. REL-1017 may exert antidepressant effects via uncompetitive 
      N-methyl-D-aspartate receptor (NMDAR) channel block. As REL-1017 is expected to 
      exert central nervous system activity, full characterization of its abuse 
      potential is warranted. We evaluated lack of reinforcing effect, physical 
      dependence, and withdrawal of REL-1017 in Sprague Dawley rats. (1) 
      Self-administration Study Rats were trained to self-administer oxycodone 
      intravenously (IV) and then were subjected to 3-day substitution tests where 
      saline, oxycodone, and REL-1017 were self-delivered IV by a fixed number of lever 
      presses; (2) Drug Discontinuation Study Rats were treated for 30 days by oral 
      gavage with vehicle, REL-1017, ketamine or morphine and evaluated for withdrawal 
      with functional observational batteries (FOBs). In the self-administration study, 
      rats treated with saline, vehicle, and all REL-1017 doses showed the typical 
      "extinction burst" pattern of response, characterized by an initial rapid 
      increase of lever-pressing followed by a rapid decrease over 3 days. Rats treated 
      with oxycodone maintained stable self-injection, as expected for reinforcing 
      stimuli. In the withdrawal study, REL-1017 did not engender either morphine or 
      ketamine withdrawal signs over 9 days following abrupt discontinuation of drug 
      exposure. REL-1017 showed no evidence of abuse potential and did not engender 
      withdrawal symptomatology.
CI  - (c) 2022. The Author(s).
FAU - Henningfield, Jack
AU  - Henningfield J
AD  - Pinney Associates, Bethesda, MA, USA.
FAU - Gauvin, David
AU  - Gauvin D
AD  - Charles River Laboratories, Wilmington, MA, USA.
FAU - Bifari, Francesco
AU  - Bifari F
AD  - Department of Medical Biotechnology and Translational Medicine, University of 
      Milan, Milan, Italy.
FAU - Fant, Reginald
AU  - Fant R
AD  - Pinney Associates, Bethesda, MA, USA.
FAU - Shram, Megan
AU  - Shram M
AD  - Altreos Research Partners, Toronto, ON, Canada.
FAU - Buchhalter, August
AU  - Buchhalter A
AD  - Pinney Associates, Bethesda, MA, USA.
FAU - Ashworth, Judy
AU  - Ashworth J
AD  - Pinney Associates, Bethesda, MA, USA.
FAU - Lanier, Ryan
AU  - Lanier R
AD  - Pinney Associates, Bethesda, MA, USA.
FAU - Pappagallo, Marco
AU  - Pappagallo M
AD  - Relmada Therapeutics, Inc., Coral Gables, FL, USA.
FAU - Inturrisi, Charles
AU  - Inturrisi C
AD  - Relmada Therapeutics, Inc., Coral Gables, FL, USA.
FAU - Folli, Franco
AU  - Folli F
AD  - Department of Health Sciences, University of Milan, Milan, Italy.
FAU - Traversa, Sergio
AU  - Traversa S
AD  - Relmada Therapeutics, Inc., Coral Gables, FL, USA.
FAU - Manfredi, Paolo L
AU  - Manfredi PL
AD  - Relmada Therapeutics, Inc., Coral Gables, FL, USA. PManfredi@relmada.com.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220706
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (D-methadone)
RN  - 690G0D6V8H (Ketamine)
RN  - 76I7G6D29C (Morphine)
RN  - CD35PMG570 (Oxycodone)
RN  - UC6VBE7V1Z (Methadone)
SB  - IM
MH  - Animals
MH  - *Ketamine
MH  - Methadone/adverse effects
MH  - Morphine
MH  - Oxycodone/adverse effects
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - *Substance-Related Disorders
PMC - PMC9259683
COIS- This research was performed at Charles River Laboratories and was sponsored by 
      Relmada Therapeutics. Dr Gauvin is an employee at Charles River Laboratories. 
      Drs. Manfredi, Inturrisi, Pappagallo, Shram, Henningfield, Buchhalter, Ashworth, 
      Lanier, Folli are paid consultants of Relmada Therapeutics. Sergio Traversa is an 
      employee at Relmada Therapeutics. Drs Inturrisi and Manfredi are inventors on 
      esmethadone patents and other patents and patent applications. Francesco Bifari 
      has no competing interests.
EDAT- 2022/07/07 06:00
MHDA- 2022/07/09 06:00
PMCR- 2022/07/06
CRDT- 2022/07/06 23:21
PHST- 2021/11/22 00:00 [received]
PHST- 2022/05/17 00:00 [accepted]
PHST- 2022/07/06 23:21 [entrez]
PHST- 2022/07/07 06:00 [pubmed]
PHST- 2022/07/09 06:00 [medline]
PHST- 2022/07/06 00:00 [pmc-release]
AID - 10.1038/s41598-022-15055-3 [pii]
AID - 15055 [pii]
AID - 10.1038/s41598-022-15055-3 [doi]
PST - epublish
SO  - Sci Rep. 2022 Jul 6;12(1):11389. doi: 10.1038/s41598-022-15055-3.