Pharmacokinetics of morphine after intramuscular injection in common goldfish Carassius auratus and Atlantic salmon Salmo salar

Abstract

Teleost fish have a nociceptive system and likely perceive pain. This warrants the development of analgesic protocols both for experimental surgery and for various husbandry procedures. Morphine is the standard analgesic against which the efficacy of other analgesics is assessed, and is the analgesic that has been most used in fish. The aims of this study were to describe the pharmacokinetics of morphine after an intramuscular (i.m.) injection in common goldfish and Atlantic salmon, and to illustrate the whole-body distribution of morphine in salmon following i.m. injection of tritiated morphine. In the kinetic experiment, goldfish and salmon were respectively i.m. injected with 40 and 100 mg morphine kg -1 in the right dorsal epaxial musculature. Blood was drawn at predetermined time points. Plasma was analysed for morphine and metabolites using liquid chromatography-mass spectrometry (LC-MS/MS). Morphine had a T max (time at which the maximum plasma concentration was measured) of 0.5 h in both species. The C max (maximum plasma concentration) showed substantial inter-individual variation, with a mean (90% CI) of 187 (167 to 199) mg l -1 in salmon and 37 (29 to 43) mg l -1 in goldfish, as determined by bootstrap analysis. The mean elimination half-lives were 12.5 and 13.5 h in goldfish and in salmon, respectively. The degree of metabolism to morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) was low, with levels of M3G exceeding those of M6G. The distribution study demonstrated that the levels of tritiated morphine in the anterior kidney surpassed those in the other organs. A substantial amount seemed to be excreted through the gastrointestinal tract, while little tritium activity could be detected in the central nervous system. KEY WORDS: Morphine · Teleost · Goldfish · Salmon · Distribution · Autoradiography Resale or republication not permitted without written consent of the publisherDis Aquat Org 88: [55][56][57][58][59][60][61][62][63] 2009 fish have focused on morphine. In rainbow trout, goldfish and winter flounder, morphine has shown antinociceptive effects (Ehrensing et al. 1982, Sneddon 2003, Newby et al. 2007, Newby et al. 2009). However, the doses used have been high compared to those needed to obtain effects in mammals, with 40 to 3000 mg morphine kg -1 being injected intraperitoneally or intramuscularly in fish, compared to 1 mg kg -1 for rats (King et al. 2007). The few existing studies on the pharmacokinetics of opioids in fish have revealed interspecific differences in the disposition of morphine (Newby et al. 2006, Newby et al. 2008, Newby et al. 2009). Therefore, more research is needed on the pharmacokinetics of morphine and its metabolites in different fish species before analgesic protocols can be suggested and validated.In humans, morphine is metabolized in several ways, the most important of which being its conjugation with glucuronic acid in the liver (Andersen et al. 2003). In humans, 44 to 55% of morphine is metabolised to morphine-3-glucuronide (M3G), 8 to 10%...

Can fish really feel pain?

“…It should also be noted that following tritiated morphine injection in Atlantic salmon Salmo salar (Salmonidae), Nordgreen et al . () failed to find much of the isotope in central nervous system, most being in the head kidney. Sneddon () states ‘morphine sulfate (0.3 g/1 mL sterile saline) was injected intramuscularly (0.1 mL/10 g fish weight).’ This is equivalent to 10 mL kg −1 or 3000 mg of morphine kg −1 .…”

“…In addition, the morphine dosage used by Sneddon et al (2003b) was exceedingly high . It should also be noted that following tritiated morphine injection in Atlantic salmon Salmo salar (Salmonidae), Nordgreen et al (2009b) failed to find much of the isotope in central nervous system, most being in the head kidney. Sneddon (2003b) states 'morphine sulfate (0.3 g/1 mL sterile saline) was injected intramuscularly (0.1 mL/ 10 g fish weight).'…”

Welfare and stress in fish

“…(2009), which tested morphine and had demonstrated pain perception in these fishes. [29,30] Studies have demonstrated, after injury in medial and lateral pallium, avoiding behavioral learning in goldfish and showing involvement by these telencephalic structures in this process. [31,32] Asphyxia on ice or evisceration without any anesthesia are common examples of killing methods used in fish farming.…”

Simultaneous analysis of gemfibrozil, morphine, and its two active metabolites in different mouse brain structures using solid‐phase extraction with ultra‐high performance liquid chromatography and tandem mass spectrometry with a deuterated internal standard

“…There are several methods used to detect morphine or its main metabolites M3G and M6G in animal tissues, but not in brain samples [19][20][21][22][23][24]. However, most of them used different molecules as internal standard (IS) such as donepezil, codeine, and naloxone hydrochloride [19][20][21][22].…”