Research Index | Medline Index

Authors

Novelli GP, Peduto VA, Bertol E, Mari F, Pieraccioli E

Title

Analgesic interaction between nitrous oxide and delta-9-tetrahydrocannabinol in the rat.

Source

British Journal of Anaesthesia

Date

1983 Oct

Issue

55(10)

Pages

997-1000

Abstract

The analgesic activities of a 75:25% nitrous oxide-oxygen mixture administered for 15 min, of delta-9-tetrahydrocannabinol (THC) 10 mg kg-1 i.p., and of a combination of both, were evaluated in the rat by tail-flick and hot-plate tests. The nitrous oxide-oxygen mixture produced a significant increase in the pain threshold. The analgesic activity of THC was similar in extent but of longer duration than that of nitrous oxide. The cannabinoid also induced some locomotor and behavioural modifications. When both THC and the nitrous oxide-oxygen mixture were administered, a significant potentiation of the analgesic response was produced, without modification of the locomotor and behavioural responses that were induced by THC alone. Such mixtures may prove of value in the control of chronic pain in man.

Authors

Moss DE, Johnson RL

Title

Tonic analgesic effects of delta 9-tetrahydrocannabinol as measured with the formalin test.

Source

European Journal of Pharmacology

Date

1980 Feb 8

Issue

61(3)

Pages

313-5

Abstract

The analgesic effects of delta 9-tetrahydrocannabinol (THC), the psychoactive component of marihuana, were tested using the formalin test. Rats were treated with either THC (5 mg/kg or 10 mg/kg) or a placebo by gavage 4 h before the formalin test for analgesia was initiated. THC produced a highly significant analgesic effect against both phasic pain and tonic pain. THC is discussed as a model for the development of new analgesics or as a suitable analgesic if used with another potentiating drug.

Authors

Lichtman AH, Martin BR

Title

Spinal and supraspinal components of cannabinoid-induced antinociception.

Source

Journal of Pharmacology & Experimental Therapeutics

Date

1991 Aug

Issue

258(2)

Pages

517-23

Abstract

The purpose of this study was to investigate whether cannabinoids produce antinociception spinal and supraspinal sites of action. The antinociceptive effect of delta 9-tetrahydrocannabinol (3 or 10 mg/kg), a naturally occurring cannabinoid, and CP-55,940 (0.1, 0.3, or 0.5 mg/kg), a potent synthetic cannabinoid, were assessed in spinally transected and intact rats. Each drug, administered i.v., produced a potent, long-lasting elevation of tail-flick latencies in the intact animals. This antinociception was significantly attenuated by spinal transection. Administration of each cannabinoid (i.t.) to the lumbar region of the spinal cord produced a weak, but long-enduring antinociceptive effect. In contrast, spinal administration of CP-55,940 to the upper thoracic region failed to elevate tail-flick latencies above base-line values. Additionally, i.t. administration of CP-55,940 (30 or 100 micrograms) continued to have a weak antinociceptive effect in spinal rats. In contrast, i.t. administration of CP-56,667, the (+)-enantiomer of CP-55,940, failed to elevate tail-flick latencies above base line at a dose of 1000 micrograms, thus indicating stereoselectivity. Finally, the biodisposition of 3H-delta 9-tetrahydrocannabinol after either i.v. or i.t. administration to spinal and intact rats was also assessed. The levels of radioactivity did not differ between spinal and intact animals in either whole brain, spinal cord, or plasma when the drug was administered i.v. When the drug was administered i.t., however, surgical transection of the spinal cord led to a decreased concentration of labeled substances in the whole brain and plasma. These converging lines of evidence indicate that cannabinoids produce antinociception through multiple mechanisms at the spinal and supraspinal levels of the central nervous system.

Id Code

75208114

Authors

Noyes R Jr, Brunk SF, Avery DAH, Canter AC

Title

The analgesic properties of delta-9-tetrahydrocannabinol and codeine.

Source

Clinical Pharmacology & Therapeutics

Date

1975 Jul

Issue

18(1)

Pages

84-9

Abstract

The administration of single oral doses of delta-9-tetrahydrocannabinol (THC) to patients with cancer pain demonstrated a mild analgesic effect. At a dose of 20 mg, however, THC induced side effects that would prohibit its therapeutic use including somnolence, dizziness, ataxia, and blurred vision. Alarming adverse reactions were also observed at this dose. THC, 10 mg, was well tolerated and, despite its sedative effect, may have analgesic potential.

Id Code

75133879

Authors

Noyes R Jr, Brunk SF, Baram DA, Canter A

Title

Analgesic effect of delta-9-tetrahydrocannabinol.

Source

Journal of Clinical Pharmacology

Date

1975 Feb-Mar

Issue

15(2-3)

Pages

139-43

Abstract

A preliminary trial of oral delta-9-tetrahydrocannabinol (THC) demonstrated an analgesic effect of the drug in patients experiencing cancer pain. Placebo and 5, 10, 15, and 20 mg THC were administered double blind to ten patients. Pain relief significantly superior to placebo was demonstrated at high dose levels (15 and 20 mg). At these levels, substantial sedation and mental clouding were reported.

Id Code

75197206

Authors

Sofia RD, Vassar HB, Knobloch LC

Title

Comparative analgesic activity of various naturally occurring cannabinoids in mice and rats.

Source

Psychopharmacologia

Date

1975

Issue

40(4)

Pages

285-95

Abstract

The analgesic effectiveness of delta-9-tetrahydrocannabinol (THC), a crude marihuana extract (CME), cannabinol (CBN), cannabidiol (CBD), morphine SO-4 and aspirin following oral administration was directly compared in mice using the acetic-induced writhing and hot plate tests and the Randall-Selitto paw pressure test in rats. THC and morphine were equipotent in all tests except that morphine was significantly more potent in elevating pain threshold in the uninflamed rat hind paw. In terms of THC content, CME was nearly equipotent in the hot plate and Randall-Selitto tests, but was 3 times more potent in the acetic acid writhing test. On the other hand, CBN, like aspirin, was only effective in reducing writhing frequency in mice (3 times more potent than aspirin) and raising pain threshold of the inflamed hind paw of the rat (equipotent with aspirin). CBD did not display a significantly analgesic effect in any of the test systems used. The results of this investigation seem to suggest that both THC and CME possess narcotic-like analgesic activity similar to morphine, while CBN appears to be a non-narcotic type analgesic like aspirin.

Id Code

75214189

Authors

Wilson RS, May EL

Title

Analgesic properties of the tetrahydrocannabinols, their metabolites, and analogs.

Source

Journal of Medicinal Chemistry

Date

1975 Jul

Issue

18(7)

Pages

700-3

Abstract

The tetrahydrocannabinols from marihuana were found to have moderate analgesic activity in mice by the hot-plate test (sc administration). Of the several metabolites of these two compounds tested, only the 11-hydroxy derivatives were more potent than the parent compounds. Analogs 1 and 2 (9-demethyl relatives which cannot be metabolized to 11-hydroxy compounds), both of which produce a pharmacological profile generally similar to that of delta8- and delta9-THC, were analgesically inert. This suggests that metabolism to 11-hydroxy congeners may be necessary for the mediation of analgesic activity in the mouse hot-plate test but not for other pharmacologic effects produced by these substances which we have examined.

Id Code

91078286

Authors

Maurer M, Henn V, Dittrich A, Hofmann A

Title

Delta-9-tetrahydrocannabinol shows antispastic and analgesic effects in a single case double-blind trial.

Source

European Archives of Psychiatry & Neurological Sciences

Date

1990

Issue

240(1)

Pages

1-4

Abstract

A double-blind study was performed comparing 5 mg delta-9-tetrahydrocannabinol (THC) p.o., 50 mg codeine p.o., and placebo in a patient with spasticity and pain due to spinal cord injury. The three conditions were applied 18 times each in a randomized and balanced order. Delta-9-THC and codeine both had an analgesic effect in comparison with placebo. Only delta-9-THC showed a significant beneficial effect on spasticity. In the dosage of THC used no altered consciousness occurred.

Id Code

89007037

Authors

Formukong EA, Evans AT, Evans FJ

Title

Analgesic and antiinflammatory activity of constituents of Cannabis sativa L.

Source

Inflammation

Date

1988 Aug

Issue

12(4)

Pages

361-71

Abstract

Two extracts of Cannabis sativa herb, one being cannabinoid-free (ethanol) and the other containing the cannabinoids (petroleum), were shown to inhibit PBQ-induced writhing in mouse when given orally and also to antagonize tetradecanoylphorbol acetate (TPA)-induced erythema of mouse skin when applied topically. With the exception of cannabinol (CBN) and delta 1-tetrahydrocannabinol (delta 1-THC), the cannabinoids and olivetol (their biosynthetic precursor) demonstrated activity in the PBQ test exhibiting their maximal effect at doses of about 100 micrograms/kg. delta 1-THC only became maximally effective in doses of 10 mg/kg. This higher dose corresponded to that which induced catalepsy and is indicative of a central action. CNB demonstrated little activity and even at doses in excess of 10 mg/kg could only produce a 40% inhibition of PBQ-induced writhing. Cannabinoid (CBD) was the most effective of the cannabinoids at doses of 100 micrograms/kg. Doses of cannabinoids that were effective in the analgesic test orally were used topically to antagonize TPA-induced erythema of skin. The fact that delta 1-THC and CBN were the least effective in this test suggests a structural relationship between analgesic activity and antiinflammatory activity among the cannabinoids related to their peripheral actions and separate from the central effects of delta 1-THC.

Id Code

88143128

Authors

Mechoulam R, Lander N, Srebnik M, Breuer A, Segal M, Feigenbaum JJ, Jarbe TU, Consroe P

Title

Stereochemical requirements for cannabimimetic activity. [Review]

Source

NIDA Research Monograph

Date

1987

Issue

79

Pages

15-30

Abstract

The SAR of cannabimimetic activity in the cannabinoid series are reviewed with emphasis on the stereochemical requirements. Some new results are presented. The most important are that a, in humans, (-)-(1S)-delta-3-THC is much more active than (+)-(1R)-delta-3-THC; and b, with the 7-OH-delta-6-THC DMH enantiomers (32) and (33), the activity in several animal species resides completely in the (-)-(3R, 4R) enantiomer (32), the difference between the two enantiomers being up to several thousand times. The (3R,4R)-enantiomer (32) is much more active than delta-1- or delta-6-THC in animal tests, the exact level of activity depending on the test employed. The cannabimimetically inactive (+)-(3S,4S) enantiomer (33) was shown to be a potent analgetic in several animal tests. Thus, a complete dissociation between the cannabimimetic and the analgetic effects in a cannabinoid has been achieved, apparently for the first time.

References

30

Authors

- Vivian JA, Kishioka S, Butelman ER, Broadbear J, Lee KO, Woods JH

Title

- Analgesic, respiratory and heart rate effects of cannabinoid and opioid agonists in rhesus monkeys: antagonist effects of SR 141716A.

Language

- Eng

Date

- 1998 Aug

Issue

- 0022-3565

Source

- J Pharmacol Exp Ther

Pages

- 697-703

Country

- UNITED STATES

Abstract

- This study characterized the antinociceptive, respiratory and heart rate effects of the cannabinoid receptor agonists Delta-9- tetrahydrocannabinol (Delta-9-THC) and WIN 55212 (R)-(+)-2, 3-dihydro-5- methyl-3-[(4-morpholinyl)methyl]pyrol-[1,2,3-de]-1, 4-benzoxazin-6- yl)(1-naphtalenyl)methanone monomethanesulfonate, N-arachidonyl ethanolamide (anandamide) and the mu and kappa opioid receptor agonists heroin and U69593, alone and in conjunction with a cannabinoid receptor antagonist, SR 141716A [N-(piperidin-1-1-yl)-5-(4-chlorophenyl)-1(2, 4- dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride] and an opioid receptor antagonist, quadazocine, in rhesus monkeys (Macaca mulatta). Using 12 adult rhesus monkeys, latencies to remove the tail from a 50 degrees C water bath, respiration in 5% CO2 and heart rate were measured. When administered alone, SR 141716A (1.8, 5.6 mg/kg i.m.) did not alter nociception, respiration or heart rate. Delta-9-THC (0.1-10 mg/kg i.m.) and WIN 55212 (0.1-10 mg/kg i.m.) dose-dependently increased antinociception and dose-dependently decreased respiratory minute and tidal volumes and heart rate. These antinociceptive, respiratory and heart rate effects were reversed by SR 141716A but not by the opioid antagonist quadazocine (1 mg/kg i.m.). Anandamide (10 mg/kg i.m.) also produced antinociception. Heroin (0.01-10 mg/kg i.m.) and U69593 (0.01-3.2 mg/kg i.m.) also dose-dependently increased antinociception and decreased respiratory and heart rate measures; these effects were antagonized by quadazocine but not by SR 141716A. These results demonstrate selective and reversible antagonism of cannabinoid behavioral effects by SR 141716A in rhesus monkeys.

Research Institute

- Department of Psychology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0632, USA. jvivian@umich.edu

Source

- J Pharmacol Exp Ther 1998 Aug;286(2):697-703

Authors

- Reche I, Ruiz-Gayo M, Fuentes JA

Title

- Inhibition of opioid-degrading enzymes potentiates delta9- tetrahydrocannabinol-induced antinociception in mice [In Process Citation]

Language

- Eng

Date

- 1998

Issue

- 0028-3908

Source

- Neuropharmacology

Pages

- 215-22

Country

- ENGLAND

Abstract

- Delta9-tetrahydrocannabinol (delta9-THC) elicits antinociception in rodents through the central CB1 cannabinoid receptor subtype. In addition. Delta9-THC stimulates the release of dynorphin-related peptides leading to kappa-opioid spinal antinociception. In this work we describe the effect of a mixture of thiorphan (a neutral endopeptidase EC3.4.24.11 inhibitor) and bestatin (an aminopeptidase inhibitor), administered i.c.v., on the antinociceptive effect of peripherally administered delta9-THC in mice. As in the case of morphine or DAMGO ([D-Ala2.N-Me-Phe4,Gly-ol]enkephalin), a mu-selective opioid receptor agonist, the mixture of enkephalin-degrading enzyme inhibitors also enhanced the antinociceptive effect of delta9-THC. This effect was blocked by the CB1 cannabinoid receptor antagonist, SR- 141,716-A, as well as by naloxone. The kappa-opioid receptor antagonist nor-binaltorphimine, administered i.t., also antagonized the effect of this combination. Similar results were obtained with the mu-opioid receptor antagonist beta-funaltrexamine after i.c.v. administration. These results demonstrate the involvement of both mu-opioid supraspinal and kappa-opioid spinal receptors in the interaction of both opioid and cannabinoid systems regulating nociception in mice.

Research Institute

- Departamento de Farmacologia, Facultad de Farmacia, Universidad Complutense de Madrid, Ciudad Universitaria, Spain.

Source

- Neuropharmacology 1998;37(2):215-22

Authors

- Smith FL, Fujimori K, Lowe J, Welch SP

Title

- Characterization of delta9-tetrahydrocannabinol and anandamide antinociception in nonarthritic and arthritic rats.

Language

- Eng

Date

- 1998 May

Issue

- 0091-3057

Source

- Pharmacol Biochem Behav

Pages

- 183-91

Country

- UNITED STATES

Abstract

- Little is known about the effectiveness of delta9-tetrahydrocannabinol (THC) and anandamide in blocking mechanical nociception. Even less is known about their antinociceptive efficacy in chronic inflammatory arthritis induced by Freund's complete adjuvant. The hypothesis was tested that THC and anandamide elicit antinociception in the paw pressure test, and that arthritic rats would exhibit a different response. In nonarthritic rats, THC- and anandamide-induced antinociception lasted 90 min and 15 min, respectively, while antinociception lasted 90 min and 30 min, respectively, in arthritic rats. Area under the curve calculations revealed no effect of arthritis on THC- and anandamide-induced antinociception. Another hypothesis was that paw pressure thresholds in arthritic rats reflect chronic cannabinoid receptor stimulation due to elevations in free anandamide levels. Yet, the CB1 receptor antagonist SR141716A failed to alter paw pressure thresholds in either nonarthritic or arthritic rats. Further investigation revealed that SR141716A significantly blocked THC antinociception, with no effect on anandamide. Thus, anandamide's effects did not result from CB1 receptor stimulation, and any potential contribution of endogenous anandamide in arthritis was not revealed. Finally, THC and anandamide appear to release an as yet unknown endogenous opioid, because naloxone significantly blocked their effects. This study indicates that anandamide and THC may act at different receptor sites to modulate endogenous opioid levels in mechanical nociception.

Research Institute

- Department of Pharmacology and Toxicology, Medical College of Virginia, Richmond 23298-0613, USA.

Source

- Pharmacol Biochem Behav 1998 May;60(1):183-91

Authors

- Rowen DW, Embrey JP, Moore CH, Welch SP

Title

- Antisense oligodeoxynucleotides to the kappa1 receptor enhance delta9- THC-induced antinociceptive tolerance.

Language

- Eng

Date

- 1998 Feb

Issue

- 0091-3057

Source

- Pharmacol Biochem Behav

Pages

- 399-404

Country

- UNITED STATES

Abstract

- Delta-9-tetrahydrocannabinol produces potent antinociceptive effects in mice and rats. Evidence exists for an interaction between the cannabinoids and the kappa receptor subtype, kappa1, in the production of antinociception. Data indicate that delta9-THC induces the release of endogenous dynorphins, the ligand(s) for the kappa receptor. It has been demonstrated that antisense oligodeoxynucleotides directed against the kappa1 receptor attenuate the antinociceptive effects of delta9- THC. The exact mechanism for the expression of cannabinoid tolerance is unknown. Bidirectional cross-tolerance between the kappa opioids and delta9-THC implies that a common mechanism may be responsible for tolerance expression. We tested the hypothesis that the kappa1 receptor is involved in tolerance to delta9-THC. Antisense to the kappa1 receptor has been shown to downregulate the kappa receptor. We observed a significant increase in the ED50 for delta9-THC in antisense-, but not mismatch-treated mice, indicating an increase in tolerance to delta9-THC. Such data indicate that a decrease in kappa receptor number may accompany tolerance to delta9-THC.

Research Institute

- Department of Nurse Anesthesia, Medical College of Virginia/Virginia Commonwealth University, Richmond 23298, USA.

Source

- Pharmacol Biochem Behav 1998 Feb;59(2):399-404

Authors

- Richardson JD, Aanonsen L, Hargreaves KM

Title

- Hypoactivity of the spinal cannabinoid system results in NMDA-dependent hyperalgesia.

Language

- Eng

Date

- 1998 Jan 1

Issue

- 0270-6474

Source

- J Neurosci

Pages

- 451-7

Country

- UNITED STATES

Abstract

- Cannabinoids, such as Delta9-THC, are capable of inhibiting nociception, i.e., pain transmission, at least in part, by interacting with spinal Gi/Go-coupled cannabinoid receptors. What is not known, however, is the antinociceptive role of endogenous spinal cannabinoids. If endogenous cannabinoids modulate basal nociceptive thresholds, then alterations in this system could be involved in the etiology of certain pain states. In this report we provide evidence for tonic modulation of basal thermal nociceptive thresholds by the spinal cannabinoid system. Administration of oligonucleotides directed against CB1 cannabinoid receptor mRNA significantly reduced spinal cannabinoid binding sites and produced significant hyperalgesia when compared with a randomer oligonucleotide control. A second method used to reduce activity of the spinal cannabinoid receptor was intrathecal administration of the cannabinoid receptor antagonist SR 141716A. SR 141716A evoked thermal hyperalgesia with an ED50 of 0.0012 fmol. The SR 141716A-induced hyperalgesia was dose-dependently blocked by the administration of D-AP- 5 or MK-801, two antagonists to the NMDA receptor. These results indicate that there is tonic activation of the spinal cannabinoid system under normal conditions. Furthermore, hypoactivity of the spinal cannabinoid system results in an NMDA-dependent hyperalgesia and thus may participate in the etiology of certain chronic pain states.

Research Institute

- Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota 55455, USA.

Source

- J Neurosci 1998 Jan 1;18(1):451-7

Authors

- Martin WJ, Hohmann AG, Walker JM

Title

- Suppression of noxious stimulus-evoked activity in the ventral posterolateral nucleus of the thalamus by a cannabinoid agonist: correlation between electrophysiological and antinociceptive effects.

Language

- Eng

Date

- 1996 Oct 15

Issue

- 0270-6474

Source

- J Neurosci

Pages

- 6601-11

Country

- UNITED STATES

Abstract

- The CNS contains a putative cannabinergic neurotransmitter and an abundance of G-protein-coupled cannabinoid receptors. However, little is known about the function of this novel neurochemical system. Cannabinold agonists produce antinociception in behavioral tests, suggesting the possibility that this system serves in part to modulate pain sensitivity. To explore this possibility, the effects of the cannabinoid agonist WIN 55,212-2 on nociceptive neurons in the ventroposterolateral (VPL) nucleus of the thalamus were examined in urethane-anesthetized rats. After identification of a nociresponsive neuron, a computer-controlled device delivered graded pressure stimuli to the contralateral hindpaw. WIN 55,212-2 (0.0625, 0.125, and 0.25 mg/kg, i.v.) suppressed noxious stimulus-evoked activity of VPL neurons in a dose-dependent and reversible manner. Noxious stimulus-evoked firing was affected more than spontaneous firing. These effects were apparently mediated by cannabinoid receptors, because the cannabinoid receptor-inactive enantiomer of the drug (WIN 55,212-3, 0.25 mg/kg) failed to alter the activity of this population of cells. Administration of morphine (0.5 mg/kg, i.v.) produced effects that were very similar to those produced by the cannabinoid. WIN 55,212-2 (0.25 mg/kg, i.v.) failed to alter the responses of non-nociceptive low- threshold mechanosensitive neurons in the VPL WIN 55,212-2 produced antinociceptive effects with a potency and time course similar to that observed in the electrophysiological experiments, despite the differences in the anesthetic states of the animals used in these experiments. The antinociceptive and electrophysiological effects on VPL neurons outlasted the motor effects of the drug. Furthermore, the changes in nociceptive responding could not be attributed to changes in skin temperature. Taken together, these findings suggest that cannabinoids decrease nociceptive neurotransmission at the level of the thalamus and that one function of endogenous cannabinoids may be to modulate pain sensitivity.

Research Institute

- Schrier Research Laboratory, Department of Psychology, Brown University, Providence, Rhode Island 02912, USA.

Source

- J Neurosci 1996 Oct 15;16(20):6601-11

Authors

- Brenneisen R, Egli A, Elsohly MA, Henn V, Spiess Y

Title

- The effect of orally and rectally administered delta 9- tetrahydrocannabinol on spasticity: a pilot study with 2 patients.

Language

- Eng

Date

- 1996 Oct

Issue

- 0946-1965

Source

- Int J Clin Pharmacol Ther

Pages

- 446-52

Country

- GERMANY

Abstract

- Multiple doses of delta 9-tetrahydrocannabinol (THC) capsules (Marinol) and THC hemisuccinate suppositories were administered in 24-hour intervals to 2 patients with organically caused spasticity. After oral doses of 10-15 mg THC, peak plasma levels from 2.1 to 16.9 ng/ml THC and 74.5 to 244.0 ng/ml 11-nor-9-carboxy-delta 9-tetrahydrocannabinol (THC-COOH, major THC metabolite) were measured by GC/MS within 1-8 h and 2-8 h, respectively. After rectal doses of 2.5-5 mg THC, peak plasma levels from 1.1 to 4.1 ng/ml THC and 6.1 to 42.0 ng/ml THC-COOH were measured within 2-8 h and 1-8 h, respectively. The bioavailability resulting from the oral formulation was 45-53% relative to the rectal route of administration, due to a lower absorption and higher first- pass metabolism. The effect of THC on spasticity, rigidity, and pain was estimated by objective neurological tests (Ashworth scale, walking ability) and patient self-rating protocols. Oral and rectal THC reduced at a progressive stage of illness the spasticity, rigidity, and pain, resulting in improved active and passive mobility. The relative effectiveness of the oral vs. the rectal formulation was 25-50%. Physiological and psychological parameters were used to monitor psychotropic and somatic side-effects of THC. No differences in the concentration ability, mood, and function of the cardiovascular system could be observed after administration of THC.

Research Institute

- Institute of Pharmacy, University of Bern, Switzerland.

Source

- Int J Clin Pharmacol Ther 1996 Oct;34(10):446-52