European College of
Neuropsychopharmacology
Zinc reduces morphine dependence with no effect on pain
perception in rats - possible beneficial role of zinc supplementation
in opioid-users
28th ECNP Congress
29 August – 1 September
2015
Diana Ciubotariu1, Cristina Mihaela Ghiciuc1, Liliana Mititelu-Tarțău1, Călin Vasile Andrițoiu2, Cătălina Elena Lupușoru1
1 Pharmacology Department, University of Medicine and Pharmacy “Grigore T. Popa” Iași, Romania
1 Nutrition Department, Western University “Vasile Goldiș” Iași , Romania
Correspondence to: diana.ciubotariu@umfiasi.ro
Basic and clinical neuroscience – Neuropharmacology
31 August 2015
Time: 12.15-13.45 hours
P.1.g.054
Results Results
Aim
- to investigate zinc sulfate (oral
administration) effect on the acute analgesic
action of a high morphine dose in tolerant
rats.
Background
Previous studies of ours: ZnSO4 → a reduction
of morphine-dependence intensity (evaluated by
Gellert-Holzmann Score of naloxone precipitated
withdrawal).
There are important evidences that Zn2+
reduces the affinity of agonists (both endogenous
& exogenous) & antagonists to μ opioid receptors
[1] & receptors density [2, 3], our findings are
probably related to Zn2+ properties of influencing
opioids action at receptor level.
On the other hand:
• opioid analgesia is recommended in patients
with final stages malignant tumors;
• Zn2+ deficiency → a predisposing factor to
malignant tumors development & infections;
• Zn2+ → analgesic effects [4, 5].
So, the aim of the present study was to
evaluate whether Zn2+ ions effect of reducing
morphine
dependence
intensity
is
accompanied (or not) by a decrease in
morphine-analgesic efficiency in morphinedependent animals.
Morphine-dependent rats had significantly lower basal and exposure tail-flick times vs. naïve
rats. This marks a strong tolerance to morphine-analgesic effect, specific to morphine-dependence.
However, the used morphine dose determined strong analgesia in both naïve and morphinedependent animals, but the morphine analgesic effect was significantly more evident in naïve rats.
Zinc oral supplementation (14 days, 2mg/kg & 4 mg/kg ZnSO4, determined just a slight, nonsignificant decrease in the analgesic effect of morphine in both naïve and morphine-dependent /
tolerant rats.
Method
Discussions
Subjects → adult Wistar male rats (groups of 10 animals each), weighting 180-250g. A cycle of 12h light
& 12h dark was induced; testing was performed during the light period.
Zinc supplimentation → zinc sulphate (ZnSO4), orally, for 14 days, previously to
morphine-dependence induction:
1) 2 mg/kg/day (B groups);
2) 4 mg/kg/day (C groups).
Morphine dependence (after 14 days of zinc → in groups B & C):
- schedule 1: 5-days schedule → morphine escalating doses (from 5mg/kg - day 1, 10mg/kg – day 2,
then the dose was increased with 10mg/kg daily up to 40 mg/kg - day 5, s.c. (daily dose split in 2
administrations daily, at 12 hours difference) (after 14 days of zinc supplimentation in groups B + C);
- schedule 2: 10-days schedule → morphine escalating doses (from 5mg/kg - day 1, 10mg/kg – day 2,
then the dose was increased with 10mg/kg daily up to 90 mg/kg - day 10, s.c. (daily dose split in 2
administrations daily, at 12 hours difference) (after 14 days of zinc supplimentation in groups B + C).
•
•
Pain sensibility → tail-flick analgesimeter:
basal latency – 30 minutes before morphine administration
exposure latency – 30 minutes after morphine administration.
Cut-off time: 20 seconds.
Morphine doses:
non-dependent subgroups: 5mg/kg (after 14 days of zinc supplimentation in groups B + C);
dependent subgroups, schedule 1: 10 mg/kg, day 6 after first morphine-dose used for dependence
induction;
dependent subgroups, schedule 2: 15 mg/kg, day 11 after first morphine-dose used for dependence
induction.
•
•
•
Zinc administration during morphine-dependence development in
rats decreases the dependence intensity, but has no significant influence
on the analgesic properties of an acute morphine dose.
Considering the low toxicity of small doses of zinc and the frequent
association between zinc deficiency and malignant tumors development, we
considered that dietary zinc supplementation might be beneficial in
patient receiving opioid therapy for cancer-related chronic pain, as it is
supposed to decrease dependence risk without affecting its pain-reducing
efficiency and have minimal side effects.
The main contra-argument is related to zinc possible effect of reducing
the opioids analgesic potency in tolerant persons.
Further animal studies and clinical investigations are needed.
References
Groups:
Groups A – normal diet;
Groups B – zinc supplementation, 2 mg/kg/day ZnSO4;
Groups C – zinc supplementation, 4 mg/kg/day ZnSO4.
For each groups, we had 3 subgroups:
- non-dependent
- morphine-dependent, schedule 1;
- morphine- dependent, schedule 2.
This schedule of zinc administration was previously shown to reduce naloxoneprecipitated morphine withdrawal.
[1] Ogawa, N., Mizuno, S., Fukushima M., Mori A., 1985. Effects of guanine nucleotides, transition metals and
temperature on enkephalin receptors of rat brain membranes. Peptides 6 Suppl 1, 23–28.
[2] Tejwani, G.A., Hanissian, S.H., 1990. Modulation of mu, delta and kappa opioid receptors in rat brain by
metal ions and histidine. Neuropharmacology 29, 445–452.
[3] Stengaard-Pedersen, K, 1982. Inhibition of enkephalin binding to opiate receptors by zinc ions: possible
physiological importance in the brain. Acta Pharmacol Toxicol (Copenh) 50: 213–20.
[4] Nozaki, C., Vergnano, A.M., Filliol, D., Ouagazzal, A.M., Le Goff, A., Carvalho, S., Reiss, D., GaveriauxRuff, C., Neyton, J., Paoletti, P., Kieffer, B.L., 2011. Zinc alleviates pain through high-affinity binding to the
NMDA receptor NR2A subunit. Nat Neurosci 14: 1017–22.
[5] Matsunami, M., Kirishi, S., Okui, T., Kawabata, A., 2011. Chelating luminal zinc mimics hydrogen sulfideevoked colonic pain in mice: possible involvement of T-type calcium channels. Neuroscience181, 257–264.
The research
was
funded
byunder
POSDRU
grant
no. 159/1.5/S/136893
grantResources
with title:
This paper
was
published
the frame
of European
Social Found, Human
Development
Operationl
Programme
2007–2013,
projectștiințifice
no. POSDRU/159/1.5/136893.
“Parteneriat
strategic pentru
creșterea
calității
cercetării
din universitățile
medicale prin acordarea de burse doctorale și postdoctorale – DocMed.Net_2.0