Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0344307 (analgesia)
28,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prolonged exposure of rats to the synthetic cannabinoid receptor ligand, CP-55,940 (0.4 mg/kg, i.p. for 11 days), induced tolerance to analgesia, to the reduction in spontaneous locomotor activity and the incidence of splayed hind limbs. One hour after the last injection on day 11, the rats were killed and in situ hybridization was used to investigate the effect of treatment on G-protein alpha-subunit expression throughout the brain. Chronic cannabinoid exposure markedly reduced G alpha(s), G alpha(i) and G alpha(o) mRNA levels. The message for the alpha(s)-subunit was decreased in all the brain areas containing the basal autoradiographic signal; the decrease ranging from 25% in the thalamus to 45% in the mesencephalon. Also the basal G alpha(i) expression was reduced in tolerant rats showing the greatest decrease in the forebrain (63%) in the cerebellum (58%) and in the mesencephalon (38%). The reduction in G alpha(o) expression (25%) was more localized, being present only in the rostral portion of the brain (cortex, striatum and olfactory area). The alterations in alpha-subunits gene expression were not followed by any change in the amount of proteins. Our results indicate that, besides the receptor modification, alteration to the G-protein expression could be a molecular event associated with the development of cannabinoid tolerance.
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PMID:Chronic treatment with a synthetic cannabinoid CP-55,940 alters G-protein expression in the rat central nervous system. 907 60

Intraperitoneal injection of delta9-THC (7.5 mg/kg) in rats made tolerant to morphine by s.c. implantation of morphine pellets had a much greater analgesic effect than in placebo pellet plus delta9-THC treatment. To investigate whether this was due to some change in cannabinoid receptor levels and/or expression induced by chronic morphine, we designed this autoradiographic binding study coupled with in situ hybridization on sagittal sections of the treated rat brains. Binding showed a significant increase in CB1 receptor density (15%) specifically in the caudate-putamen, in parallel with a significant enhancement of CB1 mRNA in the same area (20%). We suggest that morphine chronic treatment leads to a functional modulation between the opioid and cannabinoid systems at least for analgesia in a specific area, in this case the striatum.
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PMID:Modulation of rat brain cannabinoid receptors after chronic morphine treatment. 935 46

Changes in mitogen-induced splenocyte proliferation and NK activity were evaluated after acute (1 h) and chronic (6 d) in vivo treatment of rats with the synthetic cannabinoid compound CP-55,940. At a dose of 0.4 mg/kg i.p. it significantly inhibited the splenocyte proliferative response to PHA and NK activity but half this dose (0.2 mg/kg) had no effect on immune responses. Pretreatment of rats with the cannabinoid receptor CB1 antagonist SR141716A did not antagonize the CP-55,940-induced immunosuppression, excluding the activation of this receptor subtype in the mediation of this effect. When immune function studies were done on rats tolerant to CP-55,940-induced analgesia, full tolerance also developed for the inhibition of splenocyte proliferation and NK activity. The data provided indicate that CB1 cannabinoid receptors are not involved in mediating the acute and chronic effects of cannabinoids on the immune system and suggest a possible implication of CB2 receptor although other modalities of CP-55,940 action can not be ruled out.
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PMID:Regulation of immune functions in rat splenocytes after acute and chronic in vivo treatment with CP-55,940, a synthetic cannabinoid compound. 941 70

The role of nitric oxide (NO) in the development of cannabinoid tolerance was examined by using N(omega)-nitro-L-arginine methyl ester (L-NAME) as an inhibitor of NO synthase. R(+)-[2,3-Dihydro-5-methyl-3 [(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-yl]-(1-napht halenyl)methanone mesylate (WIN 55,212-2), a cannabinoid receptor agonist, or L-NAME plus WIN 55,212-2 was acutely or chronically injected i.p. to mice and analgesia, body temperature and immobility were measured. A single injection of WIN 55,212-2 induced time- and dose-dependent analgesia, hypothermia and catalepsy. L-NAME (50 mg/kg), which per se was ineffective, administered 20 min before WIN 55,212-2 did not modify the analgesic, hypothermic and cataleptic responses to the cannabinoid. When WIN 55,212-2 was administered once a day, the animals became completely tolerant to the analgesic, hypothermic and cataleptic effects within five, seven and nine days respectively. L-NAME injected once daily 20 min before WIN 55,212-2 inhibited the development of tolerance to the hypothermic and cataleptic actions but not to the analgesic action of WIN 55,212-2. Since L-NAME given chronically by itself did not modify the analgesia, hypothermia and catalepsy induced by acute administration of WIN 55,212-2, our findings suggest L-NAME acts with some selectivity on the mechanisms involved in cannabinoid tolerance.
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PMID:A role of nitric oxide in WIN 55,212-2 tolerance in mice. 957 Apr 63

Delta9-Tetrahydrocannabinol (Delta9-THC), the major psychoactive ingredient in preparations of Cannabis sativa (marijuana, hashish), elicits central nervous system (CNS) responses, including cognitive alterations and euphoria. These responses account for the abuse potential of cannabis, while other effects such as analgesia suggest potential medicinal applications. To study the role of the major known target of cannabinoids in the CNS, the CB1 cannabinoid receptor, we have produced a mouse strain with a disrupted CB1 gene. CB1 knockout mice appeared healthy and fertile, but they had a significantly increased mortality rate. They also displayed reduced locomotor activity, increased ring catalepsy, and hypoalgesia in hotplate and formalin tests. Delta9-THC-induced ring-catalepsy, hypomobility, and hypothermia were completely absent in CB1 mutant mice. In contrast, we still found Delta9-THC-induced analgesia in the tail-flick test and other behavioral (licking of the abdomen) and physiological (diarrhea) responses after Delta9-THC administration. Thus, most, but not all, CNS effects of Delta9-THC are mediated by the CB1 receptor.
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PMID:Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CB1 receptor knockout mice. 1031 80

Although it is well known that cannabinoids produce antinociception in acute pain models, there is less information on the ability of cannabinoids to alleviate hyperalgesia. In the present study, we determined whether cannabinoids attenuated the development of hyperalgesia produced by intraplantar injection of capsaicin in rats. In normal, untreated animals, intraplantar injection of 10 microg capsaicin produces nocifensive behavior (elevation of the injected paw) suggestive of pain, an increase in the frequency of withdrawal from punctate mechanical stimuli applied to the paw (mechanical hyperalgesia) and a decrease in the latency of withdrawal from noxious heat (heat hyperalgesia). Separate groups of animals were pretreated intravenously with vehicle, the cannabinoid receptor agonist WIN 55,212-2 at doses of 1, 10, 100 or 200 microg/kg, or the enantiomer WIN 55,212-3 (100 microg/kg) 5 min before intraplantar injection of capsaicin into one paw. The duration of nocifensive behavior was measured during the first 5 min after capsaicin injection. Withdrawal responses to mechanical and heat stimuli applied to the plantar surface of both hindpaws were measured before and at 5 and 30 min after capsaicin. Pretreatment with WIN 55,212-2 produced a dose-dependent decrease in nocifensive behavior and in hyperalgesia to mechanical and heat stimuli produced by capsaicin, as compared with vehicle pretreatment. Doses of 100 and 200 microg/kg WIN 55,212-2 completely blocked the development of hyperalgesia to mechanical and heat stimuli without altering withdrawal responses on the contralateral control paw. Furthermore, these doses of WIN 55,212-2 had no effect on basal withdrawal responses to heat in animals that did not receive capsaicin. The inactive enantiomer WIN 55,212-3 did not alter the development of capsaicin-evoked pain or hyperalgesia. These data suggest that low doses of cannabinoids, which do not produce analgesia or impair motor function, attenuate chemogenic pain and possess antihyperalgesic properties.
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PMID:The cannabinoid receptor agonist WIN 55,212-2 mesylate blocks the development of hyperalgesia produced by capsaicin in rats. 1035 90

Synthetic cannabinoids produce behavioral analgesia and suppress pain neurotransmission, raising the possibility that endogenous cannabinoids serve naturally to modulate pain. Here, the development of a sensitive method for measuring cannabinoids by atmospheric pressure-chemical ionization mass spectrometry permitted measurement of the release of the endogenous cannabinoid anandamide in the periaqueductal gray (PAG) by in vivo microdialysis in the rat. Electrical stimulation of the dorsal and lateral PAG produced CB1 cannabinoid receptor-mediated analgesia accompanied by a marked increase in the release of anandamide in the PAG, suggesting that endogenous anandamide mediates the behavioral analgesia. Furthermore, pain triggered by subcutaneous injections of the chemical irritant formalin substantially increased the release of anandamide in the PAG. These findings indicate that the endogenous cannabinoid anandamide plays an important role in a cannabinergic pain-suppression system existing within the dorsal and lateral PAG. The existence of a cannabinergic pain-modulatory system may have relevance for the treatment of pain, particularly in instances where opiates are ineffective.
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PMID:Pain modulation by release of the endogenous cannabinoid anandamide. 1051 99

The midbrain periaqueductal gray (PAG) is a major site of cannabinoid-mediated analgesia in the central nervous system. In the present study, we examined the actions of cannabinoids on rat PAG neurons in vitro. In brain slices, superfusion of the cannabinoid receptor agonist WIN55,212-2 inhibited electrically evoked inhibitory and excitatory postsynaptic currents in all PAG neurons. The endogenous cannabinoid anandamide inhibited evoked inhibitory postsynaptic currents in the presence of the anandamide transport inhibitor AM404, but not in its absence. The stable anandamide analog R1-methanandamide also inhibited evoked inhibitory postsynaptic currents. WIN55,212-2 reduced the rate of spontaneous miniature inhibitory postsynaptic currents in normal and Ca(2+)-free solutions, but had no effect on their amplitude distributions or kinetics. The WIN55,212-2-induced decrease in miniature inhibitory postsynaptic current rate was concentration dependent (EC(50) = 520 nM). The effects of cannabinoids were reversed by the CB(1) receptor antagonist SR141716. WIN55,212-2 produced no change in membrane current or conductance in PAG neurons in brain slices and had no effect on Ca(2+)-channel currents in acutely isolated PAG neurons. These findings suggest that cannabinoids act via CB(1) receptors to inhibit GABAergic and glutamatergic synaptic transmission in rat PAG, although the efficacy of endogenous cannabinoids is likely to be limited by uptake and breakdown. Like mu-opioids, cannabinoids act to reduce the probability of transmitter release from presynaptic terminals via a Ca(2+)-independent mechanism. In contrast to mu-opioids, cannabinoids have no direct postsynaptic actions on PAG neurons. Thus, cannabinoids and mu-opioids are likely to produce analgesia within PAG in part by different mechanisms.
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PMID:Actions of cannabinoids on membrane properties and synaptic transmission in rat periaqueductal gray neurons in vitro. 1064 38

We characterized the pharmacological properties of the anandamide transport inhibitor N-(4-hydroxyphenyl)-arachidonamide (AM404) in rats and investigated the effects of this drug on behavioral responses associated with activation of dopamine D(2) family receptors. Rat brain slices accumulated [(3)H]anandamide via a high-affinity transport mechanism that was blocked by AM404. When administered alone in vivo, AM404 caused a mild and slow-developing hypokinesia that was significant 60 min after intracerebroventricular injection of the drug and was reversed by the CB1 cannabinoid receptor antagonist SR141716A. AM404 produced no significant catalepsy or analgesia, two typical effects of direct-acting cannabinoid agonists. However, AM404 prevented the stereotypic yawning produced by systemic administration of a low dose of apomorphine, an effect that was dose-dependent and blocked by SR141716A. Furthermore, AM404 reduced the stimulation of motor behaviors elicited by the selective D(2) family receptor agonist quinpirole. Finally, AM404 reduced hyperactivity in juvenile spontaneously hypertensive rats, a putative model of attention deficit hyperactivity disorder. The results support a primary role of the endocannabinoid system in the regulation of psychomotor activity and point to anandamide transport as a potential target for neuropsychiatric medicines.
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PMID:Reversal of dopamine D(2) receptor responses by an anandamide transport inhibitor. 1077 2

Cannabinoids produce analgesia, hypomotility, catalepsy, cognitive deficits and positive reinforcement. Moreover, Delta(9)-tetrahydrocannabinol (9-THC) and synthetic cannabinoids stimulate dopaminergic neurons and increase dopamine release in different brain areas. In order to clarify the role of endogenously released dopamine in the hypothermic response to cannabinoids, the effect of D(1) and D(2) dopamine receptor agonists and antagonists on Delta(9)-THC-induced hypothermia was studied in rats. Delta(9)-THC (2.5 and 5 mg/kg intraperitoneally [IP]) decreased body temperature in a dose-related manner. This effect was antagonized not only as expected by the CB(1) cannabinoid receptor antagonist SR 141716A (0.5 mg/kg, IP) but also, unexpectedly, by the dopaminergic D(2) receptor antagonists S(-)-sulpiride (5 and 10 mg/kg, IP) and S(-)-raclopride (1 and 3 mg/kg, IP). Conversely, the hypothermic effect of Delta(9)-tetrahydrocannabinol was potentiated by the D(2) dopamine receptor agonists (-)-quinpirole (0.025 and 0.500 mg/kg, SC) and (+)-bromocriptine (0.5 and 1 mg/kg, IP). In contrast, the Delta(9)-THC-induced hypothermic effect was not modified by either by the D(1) dopamine agonist SKF 38393 (10 mg/kg SC) or by the D(1) dopamine antagonist SCH 23390 (0.5 mg/kg SC). These results suggest that the D(2) dopamine receptors have a permissive role in the hypothermic action of cannabinoids.
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PMID:Permissive role of dopamine D(2) receptors in the hypothermia induced by delta(9)-tetrahydrocannabinol in rats. 1083 59


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