Так, я собрался с мыслями чтобы пояснить тебе за анальгин.
Цитата:
Synergistic interaction between gabapentin and metamizol in the rat formalin test
The purpose of this study was to assess the possible synergistic interaction between gabapentin and metamizol in the rat formalin test. Female Wistar rats were injected into the dorsal surface of the right hind paw with 50 microl of diluted formalin (1%). Formalin injection induced a typical flinching behavior indicating nociception. Reduction of the number of flinches was considered as antinociception. Gabapentin (10-300 mg/kg), metamizol (30-600 mg/kg), or the combination of gabapentin and metamizol were administered orally and the antinociceptive effect in the formalin test was determined. Isobolographic analyses were used to define the nature of the functional interaction between gabapentin and metamizol in a fixed-dose ratio (0.5:0.5). Gabapentin (ED30 18.3+/-7.9 mg/kg), metamizol (ED30 139.2+/-6.2 mg/kg) and fixed-dose ratio gabapentin-metamizol combinations dose-dependently reduced flinching behavior during second phase of the test.
Theoretical ED30 value for the combination estimated from the isobologram was 78.8+/-5.5 mg/kg, whereas that experimental ED30 value was 15.0+/-1.2 mg/kg. Results indicate that oral administration of gabapentin and metamizol can interact synergistically to reduce inflammatory pain in the formalin test and suggest the use of this combination to relieve pain in humans.
https://pubmed.ncbi.nlm.nih.gov/15633619/ Для снятия боли на 30% в теории нужно было бы 78мг/кг Габапентина + 78мг/кг Анальгина, однако, на практике, достаточно было 15мг/кг обоих веществ - они вступают в мощную синергию.
Цитата:
Cannabinoid CB1 receptors mediate the effects of dipyroneDipyrone is a non-steroidal anti-inflammatory drug used primarily as an analgesic and antipyretic.
Some hypothesize that dipyrone activity can modulate other pathways, including endocannabinoid signalling. Thus, the aim of the present study was to evaluate the possible role of endocannabinoids in mediating dipyrone activity. This study is based on the tetrad effects of cannabinoids, namely an antinociceptive and cataleptic state, hypolocomotion and hypothermia. Dipyrone (500 mg/kg, i.p.) treatment decreased locomotor activity, increased the latency to a thermal analgesic response and induced a cataleptic and hypothermic state. These reactions are similar to the tetrad effects caused by the cannabinoid agonist WIN 55,212-2 (3 mg/kg, i.p.).
The cannabinoid CB1 receptor antagonist AM251 (10 mg/kg, i.p.) reversed the effects of dipyrone on locomotor activity, the cataleptic response and thermal analgesia. Both AM251 (10 mg/kg, i.p.) and the transient receptor potential vanilloid 1 (TRPV1) antagonist capsazepine (10 mg/kg, i.p.) accentuated the reduction in body temperature caused by dipyrone. However, the CB2 receptor antagonist AM630 did not alter the hypothermic response to dipyrone.
These results indicate involvement of the endocannabinoid system, especially CB1 receptors, in the analgesic and cataleptic effects of dipyrone, as well as hypolocomotion. However, cannabinoid receptors and TRPV1 were not involved in the hypothermic effects of dipyrone. We hypothesize that the mechanism of action of dipyrone may involve inhibition of cyclo-oxygenase and fatty acid amide hydrolase, which together provide additional arachidonic acid as substrate for endocannabinoid synthesis or other related molecules.
This increase in endocannabinoid availability enhances CB1 receptor stimulation, contributing to the observed effects.https://pubmed.ncbi.nlm.nih.gov/25430877/ Анальгин бьёт по каннабиоидным CB1 рецепторам и если заблокировать их, то он не будет работать
Цитата:
The analgesic effect of dipyrone in peripheral tissue involves two different mechanisms: neuronal K(ATP) channel opening and CB(1) receptor activationDipyrone (metamizole) is an analgesic pro-drug used to control moderate pain. It is metabolized in two major bioactive metabolites: 4-methylaminoantipyrine (4-MAA) and 4-aminoantipyrine (4-AA). The aim of this study was to investigate the participation of peripheral CB1 and CB2 cannabinoid receptors activation in the anti-hyperalgesic effect of dipyrone, 4-MAA or 4-AA. PGE2 (100ng/50µL/paw) was locally administered in the hindpaw of male Wistar rats, and the mechanical nociceptive threshold was quantified by electronic von Frey test, before and 3h after its injection. Dipyrone, 4-MAA or 4-AA was administered 30min before the von Frey test. The selective CB1 receptor antagonist AM251, CB2 receptor antagonist AM630, cGMP inhibitor ODQ or KATP channel blocker glibenclamide were administered 30min before dipyrone, 4-MAA or 4-AA. The antisense-ODN against CB1 receptor expression was intrathecally administered once a day during four consecutive days. PGE2-induced mechanical hyperalgesia was inhibited by dipyrone, 4-MAA, and 4-AA in a dose-response manner. AM251 or ODN anti-sense against neuronal CB1 receptor, but not AM630, reversed the anti-hyperalgesic effect mediated by 4-AA (Это Анаприлин), but not by dipyrone or 4-MAA (Это тоже Анаприлин),. On the other hand, the anti-hyperalgesic effect of dipyrone or 4-MAA (Это Анаприлин), was reversed by glibenclamide or ODQ.
These results suggest that the activation of neuronal CB1, but not CB2 receptor, in peripheral tissue is involved in the anti-hyperalgesic effect of 4-aminoantipyrine. (Это Анаприлин)In addition, 4-methylaminoantipyrine mediates the anti-hyperalgesic effect by cGMP activation and KATP opening.
https://pubmed.ncbi.nlm.nih.gov/25058903/ Исследование показало что один из 2 метаболитов Анальгина, 4-аминоантипирин (4-АА) бьет по каннабиоидным CB1 рецепторам
Цитата:
Dipyrone is locally hydrolyzed to 4-methylaminoantipyrine and its antihyperalgesic effect depends on CB2 and kappa-opioid receptors activationDipyrone is an analgesic pro-drug used clinically to control moderate pain with a high analgesic efficacy and low toxicity. Dipyrone is hydrolyzed to 4-methylaminoantipyrine (4-MAA), which is metabolized to 4-aminoantipyrine (4-AA). Here, were investigate the involvement of peripheral cannabinoid CB2 and opioid receptor activation in the local antihyperalgesic effect of dipyrone and 4-MAA. The inflammatory agent, carrageenan was administered to the hindpaw of male Wistar rats, and the mechanical nociceptive threshold was quantified by electronic von Frey test. Dipyrone or 4-MAA were locally administered 2.5 h after carrageenan. Following dipyrone injection, hindpaw tissue was harvested and its hydrolysis to 4-MAA was analyzed by mass spectrometry (MS). The selective CB2 receptor antagonist (AM630), naloxone (a non-selective opioid receptor antagonist), nor-BNI (a selective kappa-opioid receptor), CTOP (a selective mu-opioid receptor), or naltrindole (a selective delta-opioid receptor) was administered 30 min prior to 4-MAA. The results demonstrate that carrageenan-induced mechanical hyperalgesia was inhibited by dipyrone or 4-MAA in a dose-dependent manner. Dipyrone administered to the hindpaw was completely hydrolyzed to 4-MAA. The antihyperalgesic effect of 4-MAA was completely reversed by AM630, naloxone and nor-BNI, but not by CTOP or naltrindole.
These data suggest that the local analgesic effect of dipyrone is mediated by its hydrolyzed bioactive form, 4-MAA and, at least in part, depends on CB2 receptor and kappa-opioid receptor activation. In conclusion, the analgesic effect of dipyrone may involve a possible interaction between the cannabinoid and opioid system in peripheral tissue.https://pubmed.ncbi.nlm.nih.gov/32057719/ А вот второй метаболит Анальгина, 4-МАА (4-метиламиноантипирин) бьет уже по каннабиоидным CB2 рецепторам и по опиоидным Каппа рецепторам.
Nor-BNI и налоксон блокируют все эффекты Анальгина.
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Он такое выкидывал и в начале терапии, в январе 23го года. Потом само прошло как-то.
Вот и я думаю с лейцином провернуть трюк, чтобы дозу снизить. Только к сожалению, думаю это максимум, что можно будет сделать. Истинный СО от габы начинается не когда её мало "внутрях", а когда её очень мало! То есть дозу можно снижать-снижать, схема еще будет работать, но в какой-то переломный момент ба-бах, всё к чертям полетит. Но и процесс этого снижения тоже болезненный будет, да блин габа это полная жопа!