Search

Background Outbred Sprague–Dawley (SD) rats are a commonly used strain in preclinical pain research. Here, we established empirically how SD rats obtained from different vendors might vary in sensitivity to injury and pharmacotherapy. Methods Chronic Constriction Injury (CCI) or complete Freund's adjuvant (CFA) hindpaw inflammation was induced in male SD rats sourced from three to four different vendors, respectively. Neuropathic hypersensitivity was evaluated over 58 days using von Frey filaments, pinprick stimulation and the hot plate test. Pharmacological sensitivity was evaluated by treatment with gabapentin (100 mg/kg, p.o.) or morphine (3 mg/kg, s.c.). CFA-induced hyperalgesia and sensitivity to morphine (0.3–6 mg/kg, s.c.) was measured using a digital Randall–Selitto device. In addition, paw weight gain was used as an index of peripheral oedema. Results Significant differences between the vendor-supplied SD rats in relation to onset, magnitude and resolution of hypersensitivity after CCI were observed. Although all sub-strains eventually developed a robust and reversible neuropathic hypersensitivity to mechanical stimulation, the thermal hypersensitivity varied. Whereas pharmacological response to gabapentin varied enormously, the response to morphine was both robust and much more consistent between sub-strains. Despite a similar degree of CFA-induced hypersensitivity, the paw oedema level differed between sub-strains. Here, morphine dose-dependently alleviated the CFA-induced hypersensitivity, with only a subtle difference in sensitivity between sub-strains observed. Conclusions Our data reveal that the source of vendor used to obtain SD rats may be one key factor responsible for ‘between laboratory variation’ in reproducing sensitivity to some drugs targeting various pathophysiological mechanisms in specific animal pain models. Significance The choice of vendor used to source the same strain of rat for use in preclinical, BACKGROUND: Outbred Sprague-Dawley (SD) rats are a commonly used strain in preclinical pain research. Here, we established empirically how SD rats obtained from different vendors might vary in sensitivity to injury and pharmacotherapy.METHODS: Chronic Constriction Injury (CCI) or complete Freund's adjuvant (CFA) hindpaw inflammation was induced in male SD rats sourced from three to four different vendors, respectively. Neuropathic hypersensitivity was evaluated over 58 days using von Frey filaments, pinprick stimulation and the hot plate test. Pharmacological sensitivity was evaluated by treatment with gabapentin (100 mg/kg, p.o.) or morphine (3 mg/kg, s.c.). CFA-induced hyperalgesia and sensitivity to morphine (0.3-6 mg/kg, s.c.) was measured using a digital Randall-Selitto device. In addition, paw weight gain was used as an index of peripheral oedema.RESULTS: Significant differences between the vendor-supplied SD rats in relation to onset, magnitude and resolution of hypersensitivity after CCI were observed. Although all sub-strains eventually developed a robust and reversible neuropathic hypersensitivity to mechanical stimulation, the thermal hypersensitivity varied. Whereas pharmacological response to gabapentin varied enormously, the response to morphine was both robust and much more consistent between sub-strains. Despite a similar degree of CFA-induced hypersensitivity, the paw oedema level differed between sub-strains. Here, morphine dose-dependently alleviated the CFA-induced hypersensitivity, with only a subtle difference in sensitivity between sub-strains observed.CONCLUSIONS: Our data reveal that the source of vendor used to obtain SD rats may be one key factor responsible for 'between laboratory variation' in reproducing sensitivity to some drugs targeting various pathophysiological mechanisms in specific animal pain models.SIGNIFICANCE: The choice of vendor used to source the same strain of rat for use in preclinical pain

BACKGROUND AND PURPOSE: The 5-HT7 receptor is a GPCR that is the target of a broad range of antidepressant and antipsychotic drugs. Various studies have demonstrated an ability of the 5-HT7 receptor to modulate glutamatergic neurotransmission and cognitive processes although the potential impact upon AMPA receptors has not been investigated directly. The purposes of the present study were to investigate a direct modulation of the GluA1 AMPA receptor subunit and determine how this might influence AMPA receptor function. EXPERIMENTAL APPROACH: The influence of pharmacological manipulation of the 5-HT7 receptor system upon phosphorylation of GluA1 subunits was assessed by Western blotting of fractionated proteins from hippocampal neurones in culture (or proteins resident at the neurone surface) and the functional impact assessed by electrophysiological recordings in rat hippocampus in vitro and in vivo. KEY RESULTS: 5-HT7 receptor activation increased cAMP and relative pCREB levels in cultures of rat hippocampal neurones along with an increase in phosphorylation (Ser845) of the GluA1 AMPA receptor subunit evident in whole neurone extracts and within the neurone surface compartment. Electrophysiological recordings in rat hippocampus demonstrated a 5-HT7 receptor-mediated increase in AMPA receptor-mediated neurotransmission in vitro and in vivo. CONCLUSIONS AND IMPLICATIONS: The 5-HT7 receptor-mediated phosphorylation of the GluA1 AMPA receptor provides a molecular mechanism consistent with the 5-HT7 receptor-mediated increase in AMPA receptor-mediated neurotransmission.