The analgesic efficacy of morphine varies with rat strain and experimental pain model: implications for target validation efforts in pain drug discovery

Abstract

Background Translating efficacy of analgesic drugs from animal models to humans remains challenging. Reasons are multifaceted, but lack of sufficiently rigorous preclinical study design criteria and phenotypically relevant models may be partly responsible. To begin to address this fundamental issue, we assessed the analgesic efficacy of morphine in three inbred rat strains (selected based on stress reactivity and affective/pain phenotypes), and outbred Sprague Dawley ( SD ) rats supplied from two vendors. Methods Sensitivity to morphine (0.3–6.0 mg/kg, s.c.) was evaluated in the hot plate test of acute thermal nociception, the Complete Freund's Adjuvant ( CFA ) model of inflammatory‐induced mechanical hyperalgesia, and in a locomotor motility assay in male rats from the following strains; Lewis ( LEW ), Fischer (F344), Wistar Kyoto ( WKY ), and SD 's from Envigo and Charles River. Results F344 and SD rats were similarly sensitive to morphine in hot plate and CFA ‐induced inflammatory hyperalgesia (Minimum Effective Dose ( MED ) = 3.0 mg/kg). WKY rats developed a less robust mechanical hypersensitivity after CFA injection, and were less sensitive to morphine in both pain tests ( MED = 6.0 mg/kg). LEW rats were completely insensitive to morphine in the hot plate test, in contrast to the reversal of CFA ‐induced hyperalgesia ( MED = 3.0 mg/kg). All strains exhibited a dose‐dependent reduction in locomotor activity at 3.0–6.0 mg/kg. Conclusion Sensory phenotyping in response to acute thermal and inflammatory‐induced pain, and sensitivity to morphine in various inbred and outbred rat strains indicates that different pathophysiological mechanisms are engaged after injury. This could have profound implications for translating preclinical drug discovery efforts into pain patients. Significance The choice of rat strain used in preclinical pain research can profoundly affect the outcome of experiments in relation to (a) nociceptive threshold responses, and (b) efficacy to analgesic treatment, in assays of acute and tonic inflammatory nociceptive pain.

The influence of rat strain on the development of neuropathic pain and comorbid anxio-depressive behaviour after nerve injury

“…When investigating behavioural correlates of pain and anxio-depressive comorbidity preclinically, either inbred mouse-strains, like C57BL/6, or outbred rat strains like Sprague-Dawley (SD) or Wistar are commonly used. Previous studies in our group have demonstrated clear strain-differences in sensory thresholds of naïve rats to nociceptive stimulation, and thereafter in their functional responsiveness to inflammatory-and neuropathicinjury 22,26 . Furthermore, we also reported that the μ-opioid receptor agonist morphine possessed distinct analgesic profiles across various inbred and outbred rat strains both in the absence and presence of tissue injury 26 .…”

“…Previous studies in our group have demonstrated clear strain-differences in sensory thresholds of naïve rats to nociceptive stimulation, and thereafter in their functional responsiveness to inflammatory-and neuropathicinjury 22,26 . Furthermore, we also reported that the μ-opioid receptor agonist morphine possessed distinct analgesic profiles across various inbred and outbred rat strains both in the absence and presence of tissue injury 26 . Taken together, these observations suggest that strains with genetic predisposition to stress hyper-reactivity, depressive-or anxiety-like phenotypes could possess a higher translational value when assessing emotional comorbid burden as experienced by human pain patients.…”

Antinociceptive and Abuse Potential Effects of Cannabinoid/Opioid Combinations in a Chronic Pain Model in Rats

“…Opioids such as morphine are potent and widely used analgesics. They are considered to be the drugs of choice for the treatment of moderate to severe pain [1]. However, the use of opioids has been limited due to their unfavorable effects such as abuse liability [2].…”

Anxiety enhances pain in a model of osteoarthritis and is associated with altered endogenous opioid function and reduced opioid analgesia

“…Western blotting revealed no significant differences in total spinal MOR 394 expression in any group ( Figure 4B&C both strains of rats, it is likely that this results from reduced efficacy of opioid 430 signalling in WKY rats. Reduced efficacy of morphine was previously reported in 431 acute pain tests in WKY rats (Hestehave et al, 2019). We provide the first evidence 432 of blunted opioid analgesia in a clinically-relevant model of chronic OA pain in this 433 genetic strain of rats, providing a platform to interrogate the underlying neurobiology.…”