Pharmacology, biochemistry, and behavior
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Pharmacol. Biochem. Behav. · Nov 2008
Differential effects of repeated low dose treatment with the cannabinoid agonist WIN 55,212-2 in experimental models of bone cancer pain and neuropathic pain.
Pain due to bone malignancies is one of the most difficult types of cancer pain to fully control and may further decrease the patients' quality of life. Animal models of chronic pain conditions resulting from peripheral inflammatory reactions or nerve injuries are responsive to treatment with cannabinoid agonists. However, the use of cannabinoid agonists in humans may be hampered by CNS related side effects and development of tolerance. ⋯ Furthermore, this treatment strategy was not found to induce measurable CNS related side effects or tolerance. Cancer cell viability assays and bone volume fraction assessed by micro computed tomography (microCT) demonstrated that these effects were not due to changes in cancer progression. The difference in WIN 55,212-2 efficacy between the bone cancer and neuropathic pain models may reflect the different pain generating mechanisms, which may be utilized in designing new therapeutic drugs.
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Pharmacol. Biochem. Behav. · Oct 2008
Interaction between morphine and norketamine enantiomers in rodent models of nociception.
Ketamine, one of a few clinically-available N-Methyl-D-aspartate (NMDA)-receptor antagonists, is known to improve the analgesic efficacy of opioids in humans and rodents. However, the use of ketamine in combination with opioids is mainly restricted to the perioperative setting, due to severe psychotomimetic, sedative and motor side effects. Recent data from our laboratory demonstrated that a major metabolite of ketamine, norketamine, in particular the S(+) enantiomer, had a better antinociception/side effects profile than ketamine in rats. ⋯ In the present study, morphine (a low dose) was combined with S(+)- and R(-)-norketamine (sub-antinociceptive doses) and characterized utilizing rodent models of pain including: thermal nociception (the tail-flick test), peripheral neuropathy (chronic constriction nerve injury) and tonic inflammatory pain (the formalin test). The data showed that: 1) Norketamine enhanced morphine antinociception and blocked tolerance to this effect; 2) Norketamine potentiated morphine effectiveness in the alleviation of symptoms resulting from injury to nerve (mechanical hyperalgesia, tactile allodynia) and peripheral tissue (formalin-induced nociceptive behavior); 3) S(+)-norketamine was more potent than R(-)-norketamine; 4) Antinociception was not confounded by significant side effects. Morphine-S(+)-norketamine combination drug therapy may prove clinically useful for the alleviation of acute and chronic pain of differing etiology.
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Pharmacol. Biochem. Behav. · Oct 2008
Effects of norketamine enantiomers in rodent models of persistent pain.
NMDA-receptor antagonists are potential drugs for chronic pain treatment, in particular for neuropathic pain involving central sensitization processes. Clinical use of available NMDA antagonists, such as ketamine, is limited for this indication due to its side effects (psychotomimetic, sedative, motor). There is a need for novel NMDA-receptor antagonist(s) with better analgesia/toxicity profile(s). ⋯ The antinociceptive properties resided primarily in the S(+) enantiomer. Antinociception was not accompanied by significant side effects. The present findings suggest that norketamine, in particular the S(+) enantiomer, might be a useful NMDA-receptor antagonist for treatment of chronic pain involving central sensitization.
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Pharmacol. Biochem. Behav. · Aug 2008
ReviewOrexin/hypocretin modulation of the basal forebrain cholinergic system: insights from in vivo microdialysis studies.
Since its discovery less than a decade ago, interest in the hypothalamic orexin/hypocretin system has blossomed due to the diversity and importance of the roles played by these neuropeptides. Orexin neurons have widespread projections throughout the central nervous system and intense research has focused on elucidating the pathways and mechanisms by which orexins exert their diverse array of functions. Our group has recently focused on orexin inputs to the basal forebrain cholinergic system, which plays a crucial role in cognitive--particularly attentional--function. ⋯ Orexin activation of the basal forebrain cholinergic system appears to be especially relevant in the context of homeostatic challenges, such as food deprivation. Thus, orexins can stimulate cortical cholinergic transmission which, in turn, may promote the detection and selection of stimuli related to physiological needs. In this manner, orexin interactions with the basal forebrain cholinergic system are likely to form a link between arousal and attention in support of the cognitive components of motivated behavior.
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Pharmacol. Biochem. Behav. · Jul 2008
ReviewGABA(A) receptor subtypes underlying general anesthesia.
General anesthetics produce a constellation of behavioral responses and widespread neurodepression. Recent studies have implicated the gamma-aminobutyric acid (GABA) subtype A receptor as a primary anesthetic target. During the past decade, considerable progress has been made in dissecting the behavioral effects of anesthetics according to the subunit composition of GABA(A) receptors. In this review, we describe how particular GABA(A) receptor subtypes expressed in different brain regions are critical for the expression of behavioral endpoints, such as amnesia, sedation, and hypnosis.