NAS-181

Through pharmacological manipulation of the serotonergic (5-Hydroxytryptamin, 5-HT) system, combined with behavioral analysis, we tested the hypothesis that fear responses to predictable and unpredictable threat are regulated through stimulation of 5-HT receptors (5-HT-R) in the anterodorsal section of the bed nucleus of the stria terminalis (adBNST). Local adBNST application of 5-HT1A-R antagonist WAY100635 and 5-HT1B-R antagonist NAS-181 before fear retrieval enhanced freezing, 24 h after predictable fear conditioning. In contrast, increased fear responses to unpredictable threat were blocked by 5-HT1A-R agonist Buspirone (given before conditioning or retrieval) and 5-HT1B-R agonist CP-94253 (applied before training). Prolonged fear responses were also blocked by local application of the 5-HT2A-R antagonist R-96544 before fear retrieval, and conversely, local application of the 5-HT2A-R agonist NBOH-2C-CN hydrochloride before fear retrieval enhanced freezing 24 h after predictable conditioning, indicating augmented fear responses. Activation of inhibitory 5-HT1A- or 5-HT1B-Rs and the blockade of the excitatory 5-HT2A-R before unpredictable fear conditioning significantly reduced freezing during retrieval. The results from this study suggest that modulation of inhibitory 5-HT1A/1B-R and/or excitatory 5-HT2A-R activity in the adBNST may represent potential targets for the development of new treatment strategies in anxiety disorders. In addition, this study supports the validity and reliability of the mouse model of modulated fear to predictable and unpredictable threats to study mechanisms of fear and anxiety in combination with pharmacological manipulations.

While triptans are used to treat migraine, there is evidence that they also reduce inflammation‐induced pain at the spinal level. The cellular mechanisms underlying this spinal enhancement are unknown. We examined whether inflammation alters sumatriptan modulation of synaptic transmission in the rat spinal dorsal horn.

Three to four days following intraplantar injection of complete Freund's adjuvant (CFA) or saline, whole cell recordings of evoked glutamatergic EPSCs were made from lumbar lamina I–II dorsal horn neurons in rat spinal slices

In 2‐ to 3‐week‐old animals, sumatriptan reduced the amplitude of evoked EPSCs and this was greater in slices from CFA, compared to saline‐injected rats. In CFA‐injected animals, sumatriptan increased the paired pulse ratio of evoked EPSCs and reduced the rate of spontaneous miniature EPSCs. The 5‐HT1B and 5‐HT1D agonists CP9 3129 and PNU109291 both inhibited evoked EPSCs in CFA but not saline‐injected rats. By contrast, the 5‐HT1A agonist R(+)‐8‐OH‐DPAT inhibited evoked EPSCs in saline but not CFA‐injected rats. In CFA‐injected rats, the sumatriptan‐induced inhibition of evoked EPSCs was reduced by the 5‐HT1B and 5‐HT1D antagonists NAS181 and BRL‐15572. Intriguingly, the difference in sumatriptan inhibition between CFA and saline‐injected animals was only observed in animals less than 4 weeks old.

These findings indicate that inflammation induces a developmentally regulated 5‐HT1B/1D presynaptic inhibition of excitatory transmission into the rat superficial dorsal horn. Thus, triptans could potentially act as spinal analgesic agents for inflammatory pain in the juvenile setting.