Pharmacology, biochemistry, and behavior
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Pharmacol. Biochem. Behav. · May 2011
Serotonergic lesions of the periaqueductal gray, a primary source of serotonin to the nucleus paragigantocellularis, facilitate sexual behavior in male rats.
While selective serotonin reuptake inhibitors (SSRIs) are widely used to treat anxiety and depression, they also produce profound disruptions of sexual function including delayed orgasm/ejaculation. The nucleus paragigantocellularis (nPGi), a primary source of inhibition of ejaculation in male rats, contains receptors for serotonin (5-HT). The ventrolateral periaqueductal gray (vlPAG) provides serotonin to this region, thus providing an anatomical and neurochemical basis for serotonergic regulation of the nPGi. ⋯ Removing the source of 5-HT to the nPGi facilitated genital reflexes, but not other aspects of sexual behavior, consistent with our hypothesis. Namely, 5-HT lesions produced a significant increase in the mean number of ejaculations and a significant decrease in ejaculation latency as compared to sham lesioned animals, while latency to mating and the post-ejaculatory interval did not differ. These data suggest that the serotonergic vlPAG-nPGi pathway is an important regulatory mechanism for the inhibition of ejaculation in rats and supports the hypothesis that this circuit contributes to SSRI-induced inhibition of ejaculation.
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Pharmacol. Biochem. Behav. · May 2011
Formalin-induced long-term secondary allodynia and hyperalgesia are maintained by descending facilitation.
This work analyzes the role of cholecystokinin (CCK) receptors, dynorphin A₁₋₁₇ and descending facilitation originated in the rostral ventromedial medulla (RVM) on secondary allodynia and hyperalgesia in formalin-injected rats. Formalin injection (50 μL, 1%, s.c.) produced acute nociception (lasting 1 h) and long-term secondary allodynia and hyperalgesia in ipsilateral and contralateral hind paws (lasting 1-12 days). Once established, intra-RVM administration of lidocaine at day 6, but not at 2, reversed secondary allodynia and hyperalgesia in rats. ⋯ Moreover, intrathecal administration of dynorphin antiserum reversed, but was unable to prevent, secondary allodynia and hyperalgesia in both hind paws. These results suggest that formalin-induced secondary allodynia and hyperalgesia are maintained by activation of descending facilitatory mechanisms which are dependent on CCK₂ receptors located in the RVM and spinal cord. In addition, data suggest that spinal dynorphin A₁₋₁₇ and CCK play an important role in formalin-induced secondary allodynia and hyperalgesia.
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Pharmacol. Biochem. Behav. · Apr 2011
Granulocyte-colony stimulating factor (G-CSF) induces mechanical hyperalgesia via spinal activation of MAP kinases and PI3K in mice.
Granulocyte-colony stimulating factor (G-CSF) is a current pharmacological approach to increase peripheral neutrophil counts after anti-tumor therapies. Pain is most relevant side effect of G-CSF in healthy volunteers and cancer patients. Therefore, the mechanisms of G-CSF-induced hyperalgesia were investigated focusing on the role of spinal mitogen-activated protein (MAP) kinases ERK (extracellular signal-regulated kinase), JNK (Jun N-terminal Kinase) and p38, and PI(3)K (phosphatidylinositol 3-kinase). ⋯ Furthermore, G-CSF-induced hyperalgesia was inhibited in a dose-dependent manner by intrathecal pre-treatment with ERK (PD98059), JNK (SB600125), p38 (SB202190) or PI(3)K (wortmanin) inhibitors. The co-treatment with MAP kinase and PI(3)K inhibitors, at doses that were ineffective as single treatment, significantly inhibited G-CSF-induced hyperalgesia. Concluding, in addition to systemic opioids, peripheral opioids as well as spinal treatment with MAP kinases and PI(3)K inhibitors also reduce G-CSF-induced pain.
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Pharmacol. Biochem. Behav. · Mar 2011
Randomized Controlled TrialThe safety of modafinil in combination with oral ∆9-tetrahydrocannabinol in humans.
Marijuana (cannabis) is the most widely used illicit substance globally, and cannabis use is associated with a range of adverse consequences. Currently, no medications have been proven to be effective for the treatment of cannabis addiction. The goals of this study were to examine the safety and efficacy of a potential treatment medication, modafinil, in combination with oral ∆9-tetrahydrocannabinol (THC). ⋯ Modafinil alone increased the Profiles of Mood States (POMS) subscales of vigor and tension. These findings support the safety of modafinil in combination with THC. The effects of modafinil in combination with a range of doses of THC need to be determined in future studies.
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Pharmacol. Biochem. Behav. · Mar 2011
Monosodium iodoacetate-induced osteoarthritis produces pain-depressed wheel running in rats: implications for preclinical behavioral assessment of chronic pain.
Pain stimulates some behaviors (e.g., withdrawal responses) and depresses other behaviors (e.g., feeding and locomotion). We are developing methods for testing candidate analgesics using measurements of pain-depressed behaviors. Such assays may model important aspects of clinical pain and complement traditional procedures that measure pain-stimulated behaviors. ⋯ MIA was differentially potent across assays with a potency rank: weight-bearing≥von Frey>running wheel. MIA produced greater depression of wheel running in rats with relatively high baseline running rates compared to rats with relatively low baseline running rates. The differential potency of MIA across assays and apparent rate-dependent effects in running wheels may impact our traditional interpretations of preclinical nociceptive and antinociceptive testing.