Intrathecal Catheterization and Drug Delivery in Guinea Pigs (original) (raw)
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The intrathecal (IT) route of administration represents a means to reduce the dose of morphine administered for analgesia, potentially minimizing interactions between opioid effects and experimental outcomes. Perceived technical difficulty, and previously described invasive methods, may limit its use. This report describes a minimally invasive technique for IT administration of morphine by direct transcutaneous lumbosacral puncture in rats; and assesses antinociceptive properties of morphine in anaesthetized rats. Rats ( n = 28) anaesthetized with sevoflurane (inspired fraction of sevoflurane: FiSevo = 2.4%) were randomly allocated to receive: IT morphine (0.2 mg/kg); subcutaneous (SC) morphine (3 mg/kg); SC buprenorphine (0.05 mg/kg); or SC or IT sodium chloride (NaCl). After a wash-in period (40 min), thermal nociceptive stimuli were applied at nine locations corresponding to different rostrocaudal dermatomes of the rat. Nociceptive stimulation cycles were repeated at all location...
Spinal fluid kinetics of morphine and heroin
Clinical Pharmacology and Therapeutics, 1984
Nine patients undergoing cardiopulmonary bypass surgery were given either 2 mg diamorphine or 2.5 mg morphine by intrathecal injection. Spinal fluid (sf) samples were collected over 25 min and drug concentrations measured by HPLC. Concentrations in sf were about 4000 times as great as after 1 mg/kg IV morphine. The kinetic properties of morphine and heroin in sf differed; diamorphine was removed from sf much more rapidly than morphine. Lipophilic opiates may be safer for intrathecal use because of the shorter life of substantial drug concentrations in the mobile sf phase.
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The kinetics of "C-labelled morphine and pethidine were studied by positron emission tomography (PET) at different levels of the spinal canal (C4, T4, T5, T6, L1 and L6). Studies were performed in the Rhesus monkey after intrathecal and extradural administration of the drugs at the lumbar level (L3-L4 or L+L5, seven experiments). Radioactivity 100-300 times higher than with even distribution in the body was measured initially near the site of injection for both morphine and pethidine, irrespective of the route of administration. After injection of pethidine, high activity was observed at the L6 and L1 levels, whilst the radioactive uptake was lower at T6 ( 10-20y0 of those at lumbar level). Morphine-derived "C-radioactivity showed more constant levels along the spinal canal, except at C4 where radioactivity was low. In CSE' taken from the cervical level the peaks of radioactivity of the two drugs appeared 80-1 70 min after injection. The importance of different distribution routes was quantified in a pharmacokinetic coinpartment model, using the above results. The systemic distribution was extensive, irrespective of drug or route of administration. From the site of injection the systemic distribution was at least 60 times larger than the rostra1 distribution within the spinal canal.
Intranasal Opioid Administration in Rhesus Monkeys: PET Imaging and Antinociception
The Journal of pharmacology and experimental therapeutics, 2016
The goal of this study was to evaluate the effects of intranasally administered opioids in rhesus monkeys using the tail-withdrawal assay, and to correlate these effects with measures of receptor occupancy using positron emission tomography (PET) imaging. Initial experiments characterized the antinociceptive effects of intranasal (IN) fentanyl and buprenorphine relative to intramuscular (IM) injection. Fentanyl (0.010-0.032 mg/kg) and buprenorphine (0.1-1.0 mg/kg) produced dose-dependent increases in tail-withdrawal latency that did not differ between routes of delivery. The second experiment compared the ability of IN and intravenous (IV) naloxone (NLX) to block the antinociceptive effects IV fentanyl, and to measure receptor occupancy at equipotent doses of NLX using PET imaging. IN and IV NLX (0.0032-0.032 mg/kg) produced dose-dependent decreases in fentanyl-induced antinociception. Again, there was no difference observed in overall potency between routes. PET imaging showed that...
Experiences With Morphine Injected Into the Subarachnoid Space in Sheep
Veterinary Surgery, 1996
The effects of morphine (M), 0.1 mgkg, administered into the lumbosacral subarachnoid space of sheep used for experimental stifle surgery, were investigated. In a pilot study, preservativefree morphine was administered to three sheep, morphine containing preservatives to two sheep, and saline (S) to one sheep. After recovery from anesthesia, all five sheep administered M displayed rear limb weakness. One sheep, which had received morphine containing preservatives, also licked and chewed incessantly at its flank and hindquarters during recovery. A group of 24 sheep was used to study the effects of morphine containing preservatives, injected intrathecally, on recovery from general anesthesia and hindlimb orthopedic surgery. Eight sheep received M, eight sheep received S, and eight sheep had a needle placed in the subarachnoid space without any injection (N). Times from end of anesthesia to standing varied greatly and did not differ significantly among groups (P = .73), with M sheep averaging 119 minutes; S sheep, 87 minutes; and N sheep, 83 minutes. One sheep administered M licked and chewed at its hindquarters during recovery. Another group of 24 sheep was used to study the effects of morphine containing preservatives, injected intrathecally, on postoperative lameness. Treatments were as described previously. Sheep were videotaped intermittently for 36 hours after surgery, and each sheep was scored as follows: 0 = not lame; 1 = slightly lame; and 2 = very lame. The average lameness scores, which did not differ significantly among groups (P = .21), were: M sheep, 1.07; S sheep, 0.81; and N sheep, 0.68. One sheep administered M displayed extensor spasms of the hindlimbs, and could not stand until several hours after surgery. We conclude that subarachnoid morphine at the dosage used produces no apparent benefit in sheep which have had stifle surgery, and in fact may cause detrimental side effects, such as hindlimb weakness, and pruritis or irritation of the hindquarters.
Morphine and substance P release in the spinal cord
Experimental Brain Research, 1990
In anaesthetised cats, antibody microprobes were used to measure the release of immunoreactive substance P (irSP) in the lumbar dorsal horn during noxious cutaneous stimulation or high-intensity electrical stimulation of a hind limb nerve. The major region of irSP release detected was centred on the substantia gelatinosa, with lesser release at the dorsal cord surface. Release at these sites was unchanged by systemic administration of morphine, or of morphine followed by naloxone. During superfusion of the dorsal cord surface with high concentrations of morphine, irSP release in the substantia gelatinosa region was slightly reduced and surface release was not observed, effects not reversed by systemic naloxone administration. The results suggest that the analgesic action of morphine does not involve reduced release of SP in the spinal cord.
A chronic sheep preparation for the study of drug pharmacokinetics in spinal and ventricular CSF
Journal of Pharmacological Methods, 1986
We describe a sheep preparation utilizing chronicvascular and subarachnoid catheterization and ventriculocisternal perfusion. This preparation allows simultaneous, atraumatic sampling of plasma and CSF after drug administration by the intravenous, intracerebroventricular, or lumbar intrathecal (i.t.) routes in an unanesthesized animal. This sheep preparation provides a convenient means of studying the CSF distribution of exogenous and/or endogenous substances. During intravenous infusion at a rate of 2.2 kg/kg/min, morphine appears in cisternal CSF within 15 min. The steady-state plasma concentration and CSF flux (or appearance rate) of morphine was 0.037 and 0.009 t.#min, respectively. At steady state, 0.008% of the administered dose appears in CSWmin. The coadministration of morphine, methadone, and l.74Clsucrose into the fifth lumbar subarachnoid space is associated with the simultaneous appearance of morphine and [14C]sucrose, but not methadone, in cisternal CSF. The ratio of [14C]sucrose to morphine increased by nearly sevenfold in cisternal CSF, indicating clearance of morphine relative to ]14Clsucrose as the compounds ascend in the CSF axis. The simultaneous appearance of morphine and ['4C]sucrose in cisternal CSF after lumbar subarachnoid administration indicates that morphine, like sucrose, is distributed within the CSF by bulk flow. This sheep preparation can be used to provide the quantitative data necessary for the development of pharmacokinetic-pharmacodynamic models that relate plasma and CSF concentrations of opiates to their pharmacological effects. These studies will help to provide the pharmacological rationale for the administration of opiates by novel routes for pain management in man. 278 R. Payne et al. subarachnoid space provides more direct access to the central nervous system (CNS) and allows higher cerebrospinal fluid (CSF) and CNS drug concentrations than could be achieved by systemic administration (Shapiro et al., 1975; Nordberg, 1984). The lumbar intrathecal (i.t.) and intracerebroventricular (i.c.v.) routes of administration are used to provide postoperative and obstetrical analgesia (Bromage et al., 1980; Wang et al., 1979; Lobato et al., 1983; Cousins and Mather, 1984) and to treat leptomeningeal infections (Kaiser and McGee, 1975; Mangi et al., 1977) and leptomeningeal tumor metastases (Shapiro et al., 1975; Obbens et al., 1985). Furthermore, spinal epidural and subarachnoid administration of opoids may allow selective local analgesia at the spinal cord level (Yaksh, 1981). Although the concentration of a drug in plasma and/or CSF is usually not the same as its concentration at its site of action in the CNS (at neurons or glial cells) (Goldstein et al., 1974; Maren, 1980), at steady state, a constant proportion must exist between levels of drug in CSF, plasma, and the CNS. Furthermore, the pharmacokinetics of drugs in plasma and CSF may be relevant if one can relate this to a pharmacological effect of the drug (Colburn, 1981; Dahlstrom et al., 1978; Gibaldi and Perrier, 1982; Holford and Sheiner, 1981; Sheiner et al., 1979; Wagner, 1968). Opiate drugs are still the mainstay of treatment for acute severe pain and chronic pain due to cancer (Foley, 1985). However, a major problem limiting their usefulness as analgesics is the appearance of adverse effects (especially sedation, nausea, and respiratory depression) at therapeutic doses. To provide analgesia with fewer side effects, novel routes of administration such as continuous intravenous or subcutaneous (i.v. or s.c.) infusions and spinal epidural and/or intrathecal and intraventricular administration have been proposed (Campbell et al., 1983; Coombs et al., 1983; Fraser, 1983; Lobato et al., 1983; Onofrio et al., 1981). lntrathecal opioids provide analgesia at lower doses than are required by systemic administration, but redistribution of drugs by the systemic circulation and the CSF may limit their usefulness (Max et al., 1985; Moulin et al., 1985; Cousins and Mather, 1984).