Biomedical subjects

S P Welch

Publications and source records attributed to S P Welch.

At least 19 recordsLinked to original sources

PubMed2001

The role of minoxidil on endogenous opioid peptides in the spinal cord: a putative co-agonist relationship between K-ATP openers and opioids.

ATP-gated K(+) channel openers produce antinociception that is attenuated by opioid receptor antagonists, indicating K-ATP openers produce antinociception, in part, via the release of endogenous opioid peptides. Utilizing the spinal perfusion method, male Sprague-Dawley rats were administered minoxidil intrathecally (i.t.) at doses ranging from 12.5 to 200 microg/rat for 3 min, tested for antinociception using the tail-flick test, and perfused with artificial cerebrospinal fluid (aCSF) to collect endogenous opioid peptides. Endogenous opioid peptide levels were measured by radioimmunoassay. Naltrindole, a delta-opioid receptor antagonist, at 4 mg/kg, subcutaneously (s.c.), blocked minoxidil-induced antinociception. beta-Funaltrexamine, a mu-opioid receptor antagonist, at 100 microg/rat, partially blocked minoxidil, whereas the kappa-opioid receptor antagonist nor-binaltorphimine, at a dose of 100 microg/rat, did not attenuate minoxidil. Although antagonists of the mu- and delta-opioid receptor attenuated minoxidil-induced antinociception, there was no increase in beta-endorphin, an endogenous ligand with affinity for both micro- and delta-opioid receptors or [Leu(5)]enkephalin, an endogenous ligand with affinity for delta-opioid receptors.

Adenosine Triphosphate↗

PubMed2001

Changes in opioid and cannabinoid receptor protein following short-term combination treatment with delta(9)-tetrahydrocannabinol and morphine.

Recent studies in our laboratory have shown that in mice, low doses of morphine in combination with Delta(9)-tetrahydrocannabinol (Delta(9)-THC) have a similar antinociceptive effect to high doses of morphine alone. After short-term administration of this combination, there is no behavioral tolerance to the opioid. Previous binding studies and Western analyses following chronic morphine exposure in rodent models indicate significant mu-receptor down-regulation, as well as decreased levels of receptor protein, in both brain and spinal cord regions. We hypothesized that combination-treated animals would show no receptor protein down-regulation. The levels of opioid (mu, delta, kappa) and cannabinoid (CB1) receptor protein were evaluated in mouse models of short-term exposure to Delta(9)-THC, morphine, or both drugs in combination. Western blot analysis revealed that all three types of opioid receptor protein are significantly decreased in morphine-tolerant mouse midbrain. This down-regulation was not seen in combination-treated animals. In the spinal cord, there was an up-regulation of mu-, delta-, and kappa-opioid receptor protein in combination-treated mice when compared with morphine-tolerant mice. There were no apparent changes in levels of CB1 receptor protein in midbrain regions, and there was an up-regulation of CB1 protein in the spinal cord. The data presented here indicate that there is a correlation between morphine tolerance and receptor protein regulation. A combination of Delta(9)-THC and morphine retains high antinociceptive effect without causing changes in receptor protein that may contribute to tolerance.

Animals↗

PubMed2000

Dynorphin B and spinal analgesia: induction of antinociception by the cannabinoids CP55,940, Delta(9)-THC and anandamide.

The endogenous opioid dynorphin B was evaluated for its role in cannabinoid-induced antinociception. Previous work in our laboratory has shown that the synthetic, bicyclic cannabinoid, CP55,940, induces the release of dynorphin B whilst the naturally occurring cannabinoid, Delta(9)-tetrahydrocannabinol (Delta(9)-THC), releases dynorphin A. The dynorphins contribute in part to the antinociceptive effects of both cannabinoids at the level of the spinal cord. The present study compares dynorphin B released from perfused rat spinal cord in response to acute administration of anandamide (AEA), Delta(9)-THC and CP55,940 at two time points, 10 min and 30 min post administration, and attempts to correlate such release with antinociceptive effects of the drugs. Dynorphin B was collected from spinal perfusates of rats pretreated with Delta(9)-THC, CP55,940 or AEA. The supernatant was lyophilized and the concentrations of dynorphin B were measured via radioimmunoassay. At a peak time of antinociception (10 min), CP55,940 and Delta(9)-THC induced significant two-fold increases in the release of dynorphin B. AEA did not significantly release dynorphin B. Upon a 30-min pretreatment with the drugs, no significant dynorphin B release was observed, although antinociceptive effects persisted for CP55,940 and Delta(9)-THC. Previous work indicates that Delta(9)-THC releases dynorphin A while AEA releases no dynorphin A. This study confirms that although all three test drugs produced significant antinociception at 10 min, the endocannabinoid, AEA, does not induce antinociception via dynorphin release. Thus, our data indicate a distinct mechanism which underlies AEA-induced antinociception.

Analgesia↗

PubMed2000

Comparison of [(3)H]Glyburide binding with opiate analgesia, tolerance, and dependence in ICR and Swiss-Webster mice.

Our laboratory demonstrated that morphine exhibits a modulatory control over the glyburide-binding site (sulfonylurea receptor) of the ATP-gated K(+) channel. This study evaluated the effect of chronic morphine administration on the sulfonylurea receptor during tolerance and physical dependence. ICR and Swiss-Webster mice were rendered tolerant to morphine by pellet implantation and were withdrawn by pellet removal. Alterations in the B(max) and K(D) were evaluated in mouse spinal cord using the radiolabeled ATP-gated K(+) channel blocker glyburide. The ED(50) for Swiss-Webster mice shifted from 13 to 451 mg/kg and thus they were more tolerant to morphine than ICR mice (ED(50) shift from 12 to 120 mg/kg). Swiss-Webster mice were also dependent to morphine only when the morphine pellet was in place, unlike ICR mice, which were dependent for 48 h after morphine pellet removal. Glyburide binding increased during chronic morphine treatment in Swiss-Webster mice by over 2-fold (from 294 to 635 fmol/mg of protein). This was not observed in ICR mice. In Swiss-Webster mice, chronic morphine treatment also significantly increased the K(D) by 3-fold (from 0.38 to 1.1 nM), whereas there was no change in affinity for ICR mice. Both strains of mice remained tolerant for 2 days after spontaneous withdrawal from morphine. However, the only increases in the B(max) and K(D) of glyburide were observed in Swiss-Webster mice that were highly tolerant to morphine. These results indicate that a high degree of tolerance is needed to alter ATP-gated potassium channels.

ATP-Binding Cassette Transporters↗

PubMed1999

ATP-gated K(+) channel openers enhance opioid antinociception: indirect evidence for the release of endogenous opioid peptides.

The ATP-gated K(+) channel openers - diazoxide, levcromakalim and morphine - enhance K(+) efflux by opening ATP-gated K(+) channels, thereby inducing cell hyperpolarization. Hyperpolarization decreases intracellular Ca(2+) levels, which leads to a decrease in neurotransmitter release contributing to the antinociceptive effects of the drugs. Previous findings implicate the release of endogenous opioids as the mediator of the antinociceptive effects of ATP-gated K(+) channel openers. Diazoxide and levcromakalim, administered intracerebroventricularly (i.c.v.), produced dose-dependent antinociception as determined by the tail-flick method ¿ED(50) 44 microg/mouse [95% confidence limits (CLs) from 28 to 68 microg/mouse] for diazoxide¿. Glyburide (10 microg/mouse), an ATP-gated K(+) channel antagonist, attenuated the effects of diazoxide, levcromakalim and morphine. Diazoxide- and levcromakalim-induced antinociception were both antagonized by CTOP (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr amide), a mu-opioid receptor selective antagonist, and ICI 174,864 (N, N-diallyl-Tyr-Aib-Aib-Phe-Leu), a delta-opioid receptor antagonist, but were differentially attenuated by the kappa-opioid receptor antagonist, nor-Binaltorphimine. Combinations of inactive doses of the K(+) channel openers and opioid receptor agonists produced significant antinociceptive enhancement. Diazoxide (2 microg/mouse) shifted morphine's dose-response curve 47-fold, while levcromakalim (0.1 microg/mouse) shifted the curve 27-fold. The dose-response curve of kappa-opioid receptor agonist U50,488H (trans-(+/-)-3, 4 Dichloro-N-[2-(1-pyrrolidinyl)-cyclohexyl] benzeneacetamide methane sulfonate) was shifted 106-fold by diazoxide in a parallel manner, while levcromakalim administration increased the potency of U50,488H by 15-fold. Diazoxide shifted the dose-response curve of the delta-opioid receptor agonist, DPDPE [(D-Pen(2,5))-enkephalin], leftward in a non-parallel manner, while DPDPE was 6-fold more potent when combined with levcromakalim. We hypothesize that endogenous opioids mediate ATP-gated K(+) channel opener-induced antinociception and enhancement of opioids.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1999

Synergistic interactions of endogenous opioids and cannabinoid systems.

Cannabinoids and opioids are distinct drug classes historically used in combination to treat pain. Delta(9)-THC, an active constituent in marijuana, releases endogenous dynorphin A and leucine enkephalin in the production of analgesia. The endocannabinoid, anandamide (AEA), fails to release dynorphin A. The synthetic cannabinoid, CP55,940, releases dynorphin B. Neither AEA nor CP55,940 enhances morphine analgesia. The CB1 antagonist, SR141716A, differentially blocks Delta(9)-THC versus AEA. Tolerance to Delta(9)-THC, but not AEA, involves a decrease in the release of dynorphin A. Our preclinical studies indicate that Delta(9)-THC and morphine can be useful in low dose combination as an analgesic. Such is not observed with AEA or CP55,940. We hypothesize the existence of a new CB receptor differentially linked to endogenous opioid systems based upon data showing the stereoselectivity of endogenous opioid release. Such a receptor, due to the release of endogenous opioids, may have significant impact upon the clinical development of cannabinoid/opioid combinations for the treatment of a variety of types of pain in humans.

Animals↗

PubMed1999

Antisenses to opioid receptors attenuate ATP-gated K(+) channel opener-induced antinociception.

The ATP-gated K(+) channel openers diazoxide, levcromakalim and morphine induce cell hyperpolarization by opening the K(+) channels and enhancing K(+) efflux. This hyperpolarization decreases intracellular Ca(2+) levels, lessening neurotransmitter release thus leading to antinociception. Previous findings implicate the release of endogenous opioids as the mediator of the antinociceptive effects of ATP-gated K(+) channel openers. Antisense oligodeoxynucleotides to the opioid receptor clones, which decrease the number of available receptors, were used to demonstrate the involvement of endogenous opioids in diazoxide- and levcromakalim-induced antinociception. Antisense to all three opioid receptors attenuated the effect of diazoxide, suggesting that diazoxide is inducing the release of endogenous opioids activating the mu(MOR-1)-, delta(DOR-1)-, and kappa(KOR-1)-opioid receptors. Antisense to the mu-opioid receptor clone and delta-opioid receptor clone attenuated levcromakalim-induced antinociception, indicating that endogenous opioids acting at the mu- and delta-opioid receptors are potential candidates for the mediation of the antinociceptive effects of levcromakalim.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1999

A diminution of delta9-tetrahydrocannabinol modulation of dynorphin A-(1-17) in conjunction with tolerance development.

Previous research in this laboratory concerning delta9-tetrahydrocannabinol-induced spinal antinociception indicated the critical role of dynorphin A-(1-17) in spinal antinociception following acute intrathecal (i.t.) administration. In the present study, tolerance development to delta9-tetrahydrocannabinol-induced spinal antinociception attenuated delta9-tetrahydrocannabinol-induced modulation of immunoreactive dynorphin A-(1-17). These data indicate that at lower doses of drug, desensitization of the cannabinoid receptor inhibits stimulation of downstream dynorphinergic neurons. However, at higher doses of drug, desensitization is overcome and spinal dynorphin A concentrations are increased by delta9-tetrahydrocannabinol. Antinociception in the absence of elevated dynorphin A-(1-17) levels in the tolerant rat suggests that factors other than the attenuated dynorphin release are components of antinociception in the tolerant state. The shift from the critical role of dynorphin A in cannabinoid antinociception vs. that in the non-tolerant state may indicate tolerance also at the kappa-opioid receptor, a role as yet undetermined.

Analgesics↗

PubMed1999

Cannabinoid modulation of dynorphin A: correlation to cannabinoid-induced antinociception.

Intrathecal administration of anandamide, delta9-tetrahydrocannabinol (THC) and (-)-3-[2-hydroxy-4-(1,1-dimethyheptyl)ptyl)phenyl]-4-(3-hydr oxypropyl)-cicloexan-1-ol (CP55,940) induced spinal antinociception accompanied by differential kappa-opioid receptor involvement and dynorphin A peptide release. Antinociception using the tail-flick test was induced by the classical cannabinoid THC and was blocked totally by 17,17'-bis(cyclopropylmethyl)-6',6,7,7'-tetrahydro-4,5,4'5'-diepoxy++ +-6,6'-(imino)[7,7'-bimorphinan]-3,3',14,14'-tetrol (norbinaltorphimine) indicating a significant and critical kappa-opioid receptor component. The endogenous cannabinoid, anandamide and the non-classical bicyclic cannabinoid, CP55,940, induced non-nor-BNI-sensitive effects. The N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazo le-carboxamide (SR141716A)-mediated attenuation of spinal antinociception imparted by the various cannabinoids indicates cannabinoid CB1 receptor involvement. THC-induced an enhancement of immunoreactive dynorphin A release which coincided with the onset, but not duration antinociception. The release of dynorphin A was also attenuated by SR141716A suggesting it is cannabinoid CB1 receptor-mediated. These data indicate a critical role for dynorphin A release in the initiation of the antinociceptive effects of the cannabinoids at the spinal level.

Analgesics↗

PubMed1999

A method for the determination of activated receptor phosphorylation state following in vivo drug treatment.

Reversible phosphorylation events can alter many critical cellular functions and has been hypothesized to play a role in the development of tolerance to chronically administered agonists. The technique described here was developed to assess the phosphorylation state of mu-opioid receptor protein isolated from rodent brain tissue following 4 days of continual, subcutaneously released morphine. We have adapted and combined two techniques: back-phosphorylation reactions, which make use of tissue from animal models, and phosphorylation followed by immunoprecipitation, an approach used in cell culture models. mu-receptor protein is precipitated using a receptor-specific antibody, and the protein phosphorylation state is preserved by the use of phosphatase inhibitors. Phosphorylation sites that are dephosphorylated on the isolated protein are then radiolabelled by the addition of purified cAMP-dependent protein kinase (PKA) catalytic subunit and [32P]ATP. The samples are separated by gel electrophoresis, and the resulting bands are quantified using a phosphoimager. The amount of 32P incorporated into the protein is assumed to be inversely related to the degree of phosphorylation prior to the reaction (i.e., the in vivo state of the protein). These estimates of micro-opioid receptor phosphorylation can then be correlated with a behavioral endpoint such as antinociception, to better understand the role of phosphorylation events in tolerance development.

Adenosine Triphosphate↗

PubMed1999

Enhancement mu opioid antinociception by oral delta9-tetrahydrocannabinol: dose-response analysis and receptor identification.

The antinociceptive effects of various mu opioids given p.o. alone and in combination with Delta-9-tetrahydrocannabinol (Delta9-THC) were evaluated using the tail-flick test. Morphine preceded by Delta9-THC treatment (20 mg/kg) was significantly more potent than morphine alone, with an ED50 shift from 28.8 to 13.1 mg/kg. Codeine showed the greatest shift in ED50 value when administered after Delta9-THC (139.9 to 5.9 mg/kg). The dose-response curves for oxymorphone and hydromorphone were shifted 5- and 12.6-fold, respectively. Methadone was enhanced 4-fold, whereas its derivative, l-alpha-acetylmethadol, was enhanced 3-fold. The potency ratios after pretreatment with Delta9-THC for heroin and meperidine indicated significant enhancement (4.1 and 8.9, respectively). Pentazocine did not show a parallel shift in its dose-response curve with Delta9-THC. Naloxone administration (1 mg/kg s.c.) completely blocked the antinociceptive effects of morphine p.o. and codeine p.o. The Delta9-THC-induced enhancement of morphine and codeine was also significantly decreased by naloxone administration. Naltrindole (2 mg/kg s.c.) did not affect morphine or codeine antinociception but did block the enhancement of these two opioids by Delta9-THC. No effect was seen when nor-binaltorphimine was administered 2 mg/kg s.c. before morphine or codeine. Furthermore, the enhancements of morphine and codeine were not blocked by nor-binaltorphimine. We find that many mu opioids are enhanced by an inactive dose of Delta9-THC p.o. The exact nature of this enhancement is unknown. We show evidence of involvement of mu and possibly delta opioid receptors as a portion of this signaling pathway that leads to a decrease in pain perception.

Analgesics, Non-Narcotic↗

PubMed1998

Inhibition of protein phosphatases alters the expression of morphine tolerance in mice.

Recently our laboratory found that tolerance to morphine-induced antinociception could be completely reversed with intracerebroventricular (i.c.v.) administration of a protein kinase A inhibitor, whereas intrathecal (i.t.) administration of the inhibitor produced hyperalgesia in morphine-tolerant mice. In the experiments described here, we sought to characterize further the role of phosphorylation events in supraspinal versus spinal opioid-mediated pain pathways and how such events might be involved in the development of antinociceptive tolerance. Two phosphatase inhibitors were administered centrally to determine whether they affected morphine-induced antinociception in naive or chronically morphine-treated mice. By the i.c.v. route, okadaic acid enhanced morphine-induced antinociception in tolerant mice and produced toxicity by the i.t. route. The calcineurin inhibitor ascomycin had no effect on antinociception following acute or chronic morphine treatment. These results suggest that increased activity of protein phosphatase types 1 and/or 2A in the brain may contribute to the development of morphine tolerance.

Analgesics, Opioid↗

PubMed1998

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

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.

Analgesics↗

PubMed1998

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

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.

Analgesics↗

PubMed1998

The enhancement of morphine antinociception in mice by delta9-tetrahydrocannabinol.

We have previously reported that intracerebroventricular or intrathecal administration of inactive doses of delta9-tetrahydrocannabinol (THC) greatly enhance the antinociceptive potency of morphine in the mouse tail-flick test. Experiments were conducted to test the hypothesis that morphine's potency would be enhanced in mice receiving THC and morphine by conventional per os (p.o.) and subcutaneously (s.c.) routes of administration. Antinociception was measured in the tail-flick test of radiant heat after administration of different combinations of THC and morphine p.o. and s.c. Subcutaneous administration of THC (4 and 25 mg/kg) increased the potency of s.c. morphine 8.5- and 22.3-fold, respectively, while s.c. THC (25 mg/kg) increased the potency of p.o. morphine 3.1-fold. Per os administration of THC (10 and 20 mg/kg) increased the potency of s.c. and p.o. morphine 11.4-fold and 7.6-fold, respectively. Thus, morphine's potency was significantly increased regardless of the enteral and parenteral routes of THC and morphine administration. The synthetic receptor selective cannabinoid CP-55, 940 (0.1 mg/kg, s.c.) also enhanced morphine's potency. Finally, the ability of the CB1 receptor antagonist SR141716A to antagonize the enhancement of morphine by THC indicates that THC was acting through a cannabinoid receptor mechanism.

Analgesics, Opioid↗

PubMed1998

mu-Opioid receptor down-regulation and cAMP-dependent protein kinase phosphorylation in a mouse model of chronic morphine tolerance.

Results of radioligand binding and transfected receptor studies indicate that mu-receptor down-regulation and phosphorylation may be critical to the expression of morphine tolerance. In this study, an animal model of morphine tolerance was used to correlate antinociception with changes in receptor number and phosphorylation state. mu-Opioid receptor protein was quantitated by Western immunoassay of brainstem tissue from morphine-treated mice. Degree of receptor phosphorylation was assessed using immunoprecipitation (IP) of the receptor followed by back-phosphorylation. Acutely administered morphine produced no changes in mu-receptor quantity. Chronic morphine administration resulted in a 50% reduction in receptor protein quantity over placebo-treated samples. Back-phosphorylation experiments showed a drop in cAMP-dependent protein kinase A (PKA)-induced receptor phosphorylation shortly after acute morphine administration, followed by a naloxone-reversible increase in phosphorylation of the receptor that correlated with the onset of antinociception. Chronic morphine administration resulted in a decrease in PKA-induced phosphorylation of the mu-receptor. Since it has been shown that PKA activity is enhanced in the brains of morphine-tolerant mice, this decrease in mu-receptor phosphorylation suggests that the mu-receptor may be structurally or conformationally altered in the morphine-tolerant state.

Animals↗

PubMed1998

Differential blockade of the antinociceptive effects of centrally administered cannabinoids by SR141716A.

We evaluated delta-9 tetrahydrocannabinol (Delta9-THC), delta-8 tetrahydrocannabinol (Delta8-THC), CP55,940 (CP55), 1-deoxy-11-hydroxy-Delta8-THC-dimethylheptyl (deoxy-HU210, a CB2-selective cannabinoid that also binds the CB1 receptor) and the endogenous cannabinoid anandamide (ANA) via i.c.v. and/or intrathecal (i.t.) routes of administration, alone and in combination with SR141716A (SR), a CB1 antagonist, using the tail-flick test. Our studies were performed in order better to characterize potential diversity in interactions of the cannabinoids with the cannabinoid (CB1) receptor. When SR was administered i.c.v. or i.p. before Delta9-THC, Delta8-THC or CP55 (i.c.v. or i.t.), SR was a potent antagonist and the blockade was complete (AD50 </= 8.1 microgram/mouse i.c.v. or AD50 </= 1.4 mg/kg i.p.). The AD50 values (dose of antagonist that produced a 50% antagonism of agonist effects) for blockade of Delta9-THC, Delta8-THC, CP55,940 (i.c.v. or i.t.) by SR (i.c.v. or i.p.) differed significantly for only two combinations [Delta8-THC/SR, both i.c.v. and CP55 (i.t.)/SR (i.p.)]. Conversely, SR (i.t.) produced an incomplete block of the antinociceptive effects of i.t. Delta9-THC, Delta8-THC and CP55 (AD50 = 28.6, 50.2 and 20.9 microgram/mouse, respectively). Blockade of the deoxy-HU210 (i.c.v.) by SR (either i.c.v. or i.p.) was incomplete and AD50 values could not be calculated. Although the maximal blockade of deoxy-HU210 (i.t.) by SR (i.t.) was only 50%, SR administered i.p. before deoxy-HU210 (i.t.) produced a potent and complete blockade (AD50 = 0.4 mg/kg). The effects of SR on ANA-induced antinociception were mixed. The maximal attenuation of the ANA (i.t.) by SR (i.t.) was 38%. SR (i.p.) blockade of ANA was complete, but the AD50 was 15.4 mg/kg, greater than 15-fold higher than that required to block Delta9-THC, Delta8-THC, CP55 or deoxy-HU210. In addition, SR (i.p. or i.t.) failed to block the hypothermic effects of ANA (i.t.), while completely reversing the hypothermic effects of Delta9-THC (i.t.). These data indicate that SR has a much greater efficacy at supraspinal than at spinal sites. Alternatively, such data suggest either a differential interaction of the cannabinoids at the CB1 receptor or the existence of subtypes of the CB1 receptor.

Analgesics↗

PubMed1997

Characterization of anandamide-induced tolerance: comparison to delta 9-THC-induced interactions with dynorphinergic systems.

The endogenous ligand for the cannabinoid receptor, arachidonylethanolamide (anandamide), has been shown to produce antinociception using the tail-flick test following intrathecal administration. Anandamide was administered i.p. (40 mg kg) to mice four times per day for 3 days. Tolerance developed to anandamide: the ED50 for anandamide (i.t.) was shifted from 40 (26-61) to 139 (79-248) micrograms/mouse. Anandamide-tolerant mice were cross-tolerant to delta 9-THC and CP55,940, but not cross-tolerant to mu-, delta- or kappa- opioids, including dynorphins. Conversely, delta 9-THC-tolerant mice are cross-tolerant to anandamide, CP55,940 and kappa agonists. Our data indicate that anandamide and delta 9-THC differ in the mechanisms by which they induce tolerance, in particular the interaction with endogenous dynorphinergic systems.

Analgesics↗