Biomedical subjects

T S Grabow

Publications and source records attributed to T S Grabow.

6 recordsLinked to original sources

PubMed2001

Spinal drug delivery.

Clinicians currently base decisions regarding the use of intrathecal drug therapy for chronic pain on reports from uncontrolled and retrospective studies that fail to rely on standardized outcome measures. In this article, we summarize what is known about currently administered intrathecal therapies, including opioids, gamma-aminobutyric acid agonists, alpha-2 adrenoreceptor agonists, local anesthetics (sodium channel antagonists), calcium channel antagonists, miscellaneous agents, and drug combination therapy. In addition, we offer a brief look at novel approaches that may revolutionize intrathecal drug delivery.

Analgesics↗

PubMed2001

Cervicomedullary intrathecal injection of morphine produces antinociception in the orofacial formalin test in the rat.

BACKGROUND: High cervical and medullary drug delivery has been advocated for the treatment of refractory head and neck pain in humans. Currently, parallel models in animals have not been developed to support this methodology. We combined an accepted animal model of pain of cranial origin with a novel technique of neuraxial drug delivery to address this issue. METHODS: Male Wistar rats were implanted with intrathecal catheters that were advanced cephalad through a lumbar guide cannula to the high cervical spinal cord. The orofacial formalin test was used to assess antinociception. Vehicle or morphine (1, 3, 6, 10, 30 microg) was injected intrathecally followed 10 minutes later by injection of formalin solution, 2.5%, into the vibrissal pad. Motor assessment and hemodynamic and respiratory blood gas measurements were evaluated in a separate group of animals. RESULTS: Intrathecal morphine produced a dose-dependent decrease in the first and second phases of the behavioral response (P < 0.05). The ED50 (95% confidence limits) values for the first and second phases were 6.65 microg (3.52-14.9 microg) and 3.40 microg (2.37-4.61 microg), respectively. Ten micrograms intrathecal naloxone antagonized the morphine effect (P < 0.05). Significant cardiovascular and respiratory depression was observed. No significant motor dysfunction was observed. CONCLUSIONS: Cervicomedullary injection of morphine produced antinociception in the orofacial formalin test in the rat. This animal model may be useful to assess analgesics designed for parallel clinical application in humans.

Analgesics, Opioid↗

PubMed1999

Supraspinal and spinal delta(2) opioid receptor-mediated antinociceptive synergy is mediated by spinal alpha(2) adrenoceptors.

Concurrent administration of low doses of [D-Ala(2), Glu(4)]deltorphin (DELT) in the spinal cord and rostral ventromedial medulla of the rat produces a synergistic antinociception in the tail-flick test. It was postulated that the synergistic antinociception results from an interaction of the intrathecally-administered DELT with norepinephrine released in the spinal cord as a result of the microinjection of DELT in the rostral ventromedial medulla. Three approaches were taken to test this hypothesis. The first experiment determined that microinjection of DELT in the rostral ventromedial medulla produced an increase in tail-flick latency that was partially attenuated by intrathecal administration of the alpha(2)-adrenoceptor antagonist yohimbine. These data indicated that microinjection of DELT in the medulla causes a release of norepinephrine in the spinal cord. The second experiment determined that intrathecal co-administration of DELT with the alpha(2)-adrenoceptor agonist dexmedetomidine in a 2:1 fixed dose ratio produced a synergistic antinociception in the tail-flick test. The final experiment determined that the antinociception produced by concurrent medullary and intrathecal administration of DELT was completely antagonized by intrathecal administration of yohimbine. Taken together, these findings support the hypothesis that the synergistic antinociception produced by concurrent activation of medullary and spinal delta(2) opioid receptors is mediated, in part, by endogenous norepinephrine release in the spinal cord. The norepinephrine, acting at alpha(2)-adrenoceptors, interacts in a synergistic manner with intrathecally administered DELT, acting at spinal delta(2) opioid receptors, to produce antinociception.

Adrenergic alpha-Agonists↗

PubMed1999

Interaction between medullary and spinal delta1 and delta2 opioid receptors in the production of antinociception in the rat.

Previous work supports the existence of two types of delta opioid receptor (delta1 and delta2) and a role of both subtypes in the spinal cord and the ventromedial medulla (VMM) in the production of antinociception. Although it is well established that spinal and supraspinal mu opioid receptors interact in a synergistic manner to produce antinociception, little is known about the interaction of delta opioid receptors. This study used isobolographic analysis to determine how delta1 and delta2 opioid receptors in the VMM interact with their respective receptors in the spinal cord to produce antinociception. Concurrent administration of the delta1 opioid receptor agonist [D-Pen2,D-Pen5]enkephalin at spinal and supraspinal sites in a fixed-dose ratio produced antinociception in an additive manner in the tail-flick test. In contrast, concurrent administration of very low doses of the delta2 opioid receptor agonist [D-Ala2,Glu4]deltorphin at spinal and medullary sites produced antinociception in a synergistic manner. However, as the total dose of [D-Ala2,Glu4]deltorphin increased, this interaction converted to additivity. These observations suggest that different mechanisms mediate the antinociceptive effects of different doses of delta2 opioid receptor agonists. The difference in the nature of the interaction produced by delta1 and delta2 opioid receptor agonists provides additional evidence for the existence of different subtypes of the delta opioid receptor. These results also suggest that delta2 opioid receptor agonists capable of crossing the blood-brain barrier will be more potent or efficacious analgesics than delta1 opioid receptor agonists after systemic administration.

Analgesics, Opioid↗

PubMed1990

Intrathecal somatostatin, somatostatin analogs, substance P analog and dynorphin A cause comparable neurotoxicity in rats.

Rats chronically implanted with intrathecal catheters received intrathecal injections (10 microliters followed by 10 microliters saline flush) of either saline (n = 5), somatostatin (100 micrograms, n = 10), the somatostatin analog BIM 23003 (100 micrograms, n = 5), the somatostatin analog SMS 201-995 (100 micrograms, n = 5), the substance P analog [D-Pro2, D-Trp7,9] SP (10 micrograms, n = 10), or dynorphin A (1-17) (20 nmol, n = 8). These doses (somatostatin, substance P and dynorphin A) were selected based on previous studies in which they caused significant motor deficits. Effects on thermal cutaneous nociception, behavior, motor function and spinal cord histopathology were evaluated. All peptides caused severe neurotoxicity, evidenced by flaccid hind leg paralysis and lumbar spinal neuronal degeneration, which was accompanied by an inflammatory reaction in meninges and spinal gray matter. Histopathological changes had developed within 24 h after injection of somatostatin, substance P analog and dynorphin A, showing mild to severe neuronal degeneration and mild inflammatory responses in spinal cord and meninges. Significant antinociceptive effects, due to severe neurotoxic effects, were only observed following intrathecal injection of SMS 201-995 and the substance P analog. Potential neurotoxic mechanisms of the different peptides are discussed.

Animals↗

PubMed1989

Electroencephalographic and behavioral assessment of intracerebroventricular somatostatin and a substance P analogue.

Chronically implanted rats were injected either with somatostatin (SST) lumbar intrathecally (i.t.) (100 micrograms, n = 5), into the fourth ventricle (3 micrograms, n = 5; 10 micrograms, n = 6; 30 micrograms, n = 5) or into the lateral ventricle (10 micrograms, n = 6; 30 micrograms, n = 6), or received an injection of the substance P (SP) analogue, [D-Pro2, D-Trp7,9]SP into the fourth ventricle (0.3 micrograms, n = 2; 1 micrograms, n = 4; 3 micrograms, n = 4; 10 micrograms, n = 1) or lateral ventricle (3 micrograms, n = 3). A dose-dependent EEG depressant effect was observed following fourth and lateral ventricular injections of SST and of the SP analogue. Acute death due to respiratory depression was observed following i.t. and fourth ventricular injection of SST, and fourth ventricular injection of the SP analogue. Prominent motor behavior (barrel rotation, circling, cranial stereotypies) was observed, without signs of EEG seizure activity, following intraventricular injection of both drugs. Present findings indicate neurotoxic effects of SST and SP analogue at the cerebral level.

Animals↗