Vendor-derived differences in injury-induced pain phenotype and pharmacology of Sprague-Dawley rats: Does it matter?

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 research can profoundly affect the level of nociceptive hypersensitivity and response to reference analgesics in neuropathic versus inflammatory models.

Donepezil provides positive effects to patients treated with gabapentin for neuropathic pain: an exploratory study.

BACKGROUND: The first-line medication gabapentin and the acetylcholinesterase inhibitor donepezil represent a new promising combination to improve treatment outcomes for patients with severe neuropathic pain. The drugs have previously shown synergism following co-administration in nerve-injured rats. METHODS: The clinical relevance of adding donepezil to existing gabapentin treatment in patients with post-traumatic neuropathic pain was explored in this open-label study. The study comprised two consecutive periods of minimum 6 weeks: (1) titration of gabapentin to the highest tolerable dose or maximum 2400 mg daily, and (2) addition of donepezil 5 mg once daily to the fixed gabapentin dose. Efficacy and tolerability were assessed by ratings of pain intensity, questionnaires for pain and health-related quality of life, and reporting of adverse events. Pain scores were also analysed using mixed-effects analysis with the software NONMEM to account for intersubject variability. RESULTS: Eight patients commenced treatment with donepezil, of which two withdrew because of adverse events. Addition of donepezil resulted in clinically relevant reductions of pain (> 11 units on a 0-100 scale) and improved mental wellness in three of six patients. The remaining three patients had no obvious supplemental effect. Mixed-effects analysis revealed that pain scores were significantly lower during co-administration (P < 0.0001 combination vs. monotherapy). CONCLUSION: Donepezil may provide additional analgesia to neuropathic pain patients with insufficient pain relief from gabapentin as monotherapy. The promising results support controlled clinical trials of the drug combination. The usefulness of mixed-effects analysis in small-scale trials and/or for data with high intersubject variability was also demonstrated.

The antinociceptive efficacy of buprenorphine administered through the drinking water of rats.

Postoperative pain management in laboratory animals is important for animal welfare and required under law in many countries. Frequent injection of analgesics to rodents after surgery is stressful for the animals and labour-intensive for animal care personnel. An alternative dosing scheme such as administration of analgesics in the drinking water would be desirable. However, the efficacy of a chronic oral analgesic treatment via this route has not yet been documented. This study investigated the antinociceptive efficacy of buprenorphine administered ad libitum via the drinking water of laboratory rats. The antinociceptive efficacy of buprenorphine in drinking water was compared with repeated subcutaneous injections. A comparison was also made between buprenorphine in drinking water and the combination of one single subcutaneous injection of buprenorphine followed by buprenorphine in drinking water. Antinociception was assessed by use of an analgesiometric model measuring the rats' latency time to withdrawal from a noxious heat stimulus applied to the plantar surface of the paw. Results revealed that buprenorphine in drinking water (0.056 mg/mL) induced significant increases in paw withdrawal latency times during a three-day period of administration with a maximal effect at 39 h after the start of buprenorphine administration. One single injection of buprenorphine (0.1 mg/kg s.c.) followed by buprenorphine in the drinking water (0.056 mg/mL) induced an earlier onset of antinociception than buprenorphine in drinking water alone. In contrast, buprenorphine (0.1 mg/kg s.c.) injected every 8 h over a period of three days did not result in significant increases in paw withdrawal latency times. In conclusion, our results suggest that one single subcutaneous injection of buprenorphine followed by buprenorphine in drinking water may be a viable treatment option for the relief of pain in laboratory rats, but at the doses used in this study in pain-free rats it was associated with a decrease in water intake and some behavioural changes.