Behavioural pharmacology
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Behavioural pharmacology · Dec 2014
Optimization and pharmacological characterization of a refined cisplatin-induced rat model of peripheral neuropathic pain.
Chemotherapy-induced peripheral neuropathy (CIPN) is the major dose-limiting side-effect of many front-line anticancer drugs. This study was designed to establish and pharmacologically characterize a refined rat model of cisplatin-induced CIPN. Adult male Sprague-Dawley rats received four (n=18) or five (n=18) single intraperitoneal bolus doses of cisplatin at 3 mg/kg, or saline (control group), once-weekly. ⋯ They also showed significant thermal hypoalgesia in the bilateral hindpaws. In cisplatin-treated rats with paw withdrawal thresholds of up to 6 g, single bolus doses of gabapentin and morphine produced dose-dependent analgesia, whereas meloxicam and amitriptyline lacked efficacy. We have established and pharmacologically characterized a refined rat model of CIPN that is suitable for efficacy profiling of compounds from analgesic discovery programmes.
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Behavioural pharmacology · Aug 2014
Effect of environmental cues on the behavioral efficacy of haloperidol, olanzapine, and clozapine in rats.
Previous studies have reported that context can powerfully modulate the inhibitory effect of an antipsychotic drug on phencyclidine (PCP)-induced hyperlocomotion (a behavioral test used to evaluate putative antipsychotic drugs). The present study investigated the experimental conditions under which environmental stimuli exert their influence through associative conditioning processes. Experiment 1 examined the extent to which previous antipsychotic treatment in the home cages affected a drug's ability to inhibit PCP-induced hyperlocomotion in novel motor activity test apparatus. ⋯ Thus, more exposures to the test environment under the influence of haloperidol (but not clozapine or olanzapine) caused a stronger inhibition than fewer exposures, indicating a strong environmental modulation. Collectively, these findings suggest that previous antipsychotic treatment in one environment could alter later antipsychotic-like response assessed in a different environment under certain test conditions. Therefore, whether the circumstances surrounding antipsychotic drug administration have a powerful effect on the expression of antipsychotic-like efficacy is dependent on specific experimental and drug treatment factors.
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Behavioural pharmacology · Aug 2014
Activation of the cAMP-PKA signaling pathway in rat dorsal root ganglion and spinal cord contributes toward induction and maintenance of bone cancer pain.
The objective of this study was to explore the role of cyclic adenosine monophosphate-protein kinase A (cAMP-PKA) signaling in the development of bone cancer pain in rats. Female Sprague-Dawley rats (N=48) were divided randomly into four groups: sham (n=8), tumor cell implantation (TCI) (n=16), TCI+saline (n=8), and TCI+PKA inhibitor (n=16). Bone cancer-induced pain behaviors - thermal hyperalgesia and mechanical allodynia - were tested at postoperative days -3, -1, 1, 3, 5, 7, 10, and 14. ⋯ TCI treatment also led to obvious tumor growth and bone destruction. The level of PKA mRNA in the DRG, as well as the concentration of cAMP and the activity of PKA, in both the DRG and spinal cord were significantly increased after TCI treatment (P<0.01). We conclude that the inhibition of the cAMP-PKA signaling pathway may reduce bone cancer pain.
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Behavioural pharmacology · Jun 2014
S1RA, a selective sigma-1 receptor antagonist, inhibits inflammatory pain in the carrageenan and complete Freund's adjuvant models in mice.
The therapeutic potential of S1RA (E-52862), a selective sigma-1 receptor (σ1R) antagonist, has been explored in experimental neuropathic pain, but not in inflammatory pain models. The present study investigated the effect of the intraperitoneal administration of S1RA on the hind paw withdrawal response to thermal and mechanical stimulation following an intraplantar injection of carrageenan (CARR) and complete Freund's adjuvant (CFA), which are two well-characterized models of acute and chronic inflammatory pain, respectively. S1RA fully reversed both mechanical [dose of drug that produced half of its maximal response (ED50)=35.9 and 42.1 mg/kg for CARR-induced and CFA-induced pain, respectively] and thermal (ED50=27.9 mg/kg, CARR) hypersensitivity, whereas ibuprofen (CARR, mechanical allodynia) and celecoxib (CARR, thermal hyperalgesia; CFA, mechanical allodynia) failed to reach maximum efficacy. ⋯ Unlike celecoxib and ibuprofen, which decreased paw volume significantly, CARR-induced paw oedema was not reduced by S1RA and morphine, thus suggesting that the antinociceptive effect of S1RA does not involve a major anti-inflammatory (antioedema) action. S1RA was devoid of efficacy when administered to σ1R knockout mice, thus suggesting the involvement of σ1R in the antinociceptive effects exerted by S1RA. We conclude that S1RA represents a promising novel analgesic therapy for inflammatory pain.
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Behavioural pharmacology · Apr 2014
In-vivo pharmacological evaluation of the CB1-receptor allosteric modulator Org-27569.
Several allosteric modulators (AMs) of the CB1 receptor have been characterized in vitro, including Org27569, which enhances CB1-specific binding of [H]CP55,940, but behaves as an insurmountable CB1-receptor antagonist in several biochemical assays. Although a growing body of research has investigated the molecular actions of this unusual AM, it is unknown whether these actions translate to the whole animal. The purpose of the present study was to determine whether Org27569 would produce effects in well-established mouse behavioral assays sensitive to CB1 orthosteric agonists and antagonists. ⋯ Org27569 did not elicit CB1-mediated effects alone and lacked efficacy in altering antinociceptive, cataleptic, and hypothermic actions of the orthosteric agonists anandamide, CP55,940, and Δ-tetrahydrocannabinol. Moreover, it did not alter the discriminative stimulus effects of anandamide in FAAH-deficient mice or Δ-tetrahydrocannabinol in wild-type mice in the drug discrimination paradigm. These findings question the utility of Org27569 as a 'gold standard' CB1 AM and underscore the need for the development of CB1 AMs with pharmacology that translates from the molecular level to the whole animal.