10 Matching Annotations
  1. Oct 2021
    1. The kappa agonist spiradoline failed to produce cross-sensitization, but coadministration of spiradoline prevented morphine and buprenorphine from producing cross-sensitization. The ability of spiradoline to block cross-sensitization was itself blocked by the kappa antagonist nor-binaltorphimine.

      This suggests to me that it is the opioid tolerance itself that determines cocaine sensitivity. To test this, I'd like to see a study that administers a KOR agonist after tolerance to opioids has been established, and see if this reverses cocaine sensitivity.

  2. Sep 2021
    1. Neither fentanyl (0.0003–0.02 mg/kg) nor SNC80 (0.03–0.3 mg/kg) changed either ACTH or cortisol basal levels. In contrast, U-50488H (0.01–1 mg/kg) dose-dependently stimulated ACTH and cortisol release in both male and female monkeys. Importantly, the stimulatory effects of U-50488H on the secretion of ACTH were blocked by a selective kappa opioid receptor antagonist, nor-Binaltorphimine.

      Fascinating. I'd expect mu and delta opioids to reduce cortisol, if only indirectly via relaxation.

      Likewise, it is important to understand the mechanism by which kappa agonism increases cortisol. Kappa is known for its dysphoric effects, which would naturally increase cortisol. However, kappa agonism is also consistent with extreme euphoria. This is known from reports with Salvia divinorum and Tabernanthe iboga. Whether this euphoria decreases cortisol or if it is, rather, a form of eustress is a very interesting question.

    1. 4. Allow acetone to evaporate in a dark, well-ventilated area. You will be left with a bright green powder – about 1g per 100g of leaf. This powder is about 2 parts chlorophyll to 1 part salvinorin A.

      This is incredibly useful information.

      I noticed my extract had some bitter taste and some earthy notes. I don't know what salvinorin and chlorophyll taste like, but I assume the taste comes from other impurities. However, I extracted for many minutes (10 or so); next time, I should do only the 3 minutes suggested here (3 times 1 minute).

  3. Aug 2021
    1. At lower doses (0.18 mg/kg and 0.32 mg/kg) we observed no prolonged effect on KOR binding but at 0.60 mg/kg salvinorin A induced a sustained decrease in KOR binding (BPND decreased by 40–49%) which persisted up to 2.5 h post administration, long after salvinorin A had been eliminated from the brain. These data point towards an agonist-induced adaptive response by KOR, the dynamics of which have not been previously studied in vivo with PET.

      This may partly represent the salvia "afterglow". It also demonstrates how rapidly tolerance-like mechanism can occur.

      I find it odd that 0.32 mg/kg had little prolonged effect when twice that dose had a very large effect. I'd expect more of a gradient. The graph (figure 4) shows a nonsignificant drop in KOR binding of ~13% at 1 hour at 0.32 mg/kg, which I'm certain would become statistically significant in a larger sample. Still, that's nowhere near the 45% seen at 0.6 mg/kg. At 0.18 mg/kg, we see ~9%.

      I calculated the human equivalent dose to be 6.8mg (0.6mg0.16270). This is an very high dose, so likely does not represent an accurate dose conversion.

    1. Repeated treatment with (-)U-50,488H (s.c. or i.c.v.) significantly enhanced antinociceptive effect of both mu-opioid receptor agonist (morphine) and delta-opioid receptor agonists

      Just confirming what I believed to be the case. I couldn't remember whether I'd read results of this specific sort, so I figured I should look it up. Chronic KOR agonism appears to be an ideal opioid hack.

  4. Jun 2021
    1. Individual elimination half-life values ranged from 0.6 to 3.3 hours and were independent of dose.

      This could potentially be explained due to variation in Tmax. That is to say, it may not be that half life varies dramatically. Rather, absorption into the bloodstream after intramuscular injection may be the cause. I'm no expert on IM injections.

  5. May 2021
    1. Salvinorin A, a kappa-opioid receptor agonist hallucinogen: pharmacology and potential template for novel pharmacotherapeutic agents in neuropsychiatric disorders

      I think this may be the best review of salvinorin A that I have ever looked at. I definitely need to sit down and read the full article at some point.

    1. In contrast to its acute administration, repeated salvinorin A administration did not modify dialysate DA levels. Similarly, neither basal extracellular DA levels nor DA uptake was altered. Unlike synthetic KOPr agonists, prior repeated administration of salvinorin A did not attenuate the locomotor activating effects of an acute cocaine (20 mg/kg, i.p.) challenge. However, cocaine-evoked DA overflow was enhanced.

      Fascinating and useful stuff. This is close to what I was expecting. Though, I was expecting chronic exposure to upregulate dopamine beyond baseline. If I'm understanding this correctly, it was upregulated in the sense that it enhanced the dopaminergic effects of cocaine. I've not yet read the full study.

  6. Apr 2021
    1. Repeated KOR agonist exposure, on the other hand, can result in opposing effects on the dopamine system [27], and desensitization of the KOR [28]

      If they mean what I think they mean, then this implies that chronic KOR is useful. I'll need to check citation 27.

    1. These data suggested that PAT, an indirect-acting KOR agonist, share the common pharmacological property of KOR agonists on morphine tolerance

      PAT is apparently an herbal medicine I should look into. They also imply that KOR agonists act as I expect they do, but I'll need to read the full study to be sure.

      Edit: yup, it appears that chronic KOR agonism is probably a good idea.

      from full text "Utility of KOR agonists is a promising pharmacological tool for attenuating morphine tolerance (Pan, 1998), however, it is difficult to find effective KOR agonists that are devoid of dysphoric and psychotomimetic adverse effects in humans"

      This is the cited study.