Evidence for Endogenous Opioid Dependence Related to Latent Sensitization in a Rat Model of Chronic Inflammatory Pain

Studies performed in a mouse model of chronic inflammatory pain induced by intraplantar injection of complete Freund's adjuvant (CFA) have shown that constitutive activation of the endogenous opioid signaling, besides serving as a mechanism of endogenous analgesia that tonically represses pain sensitization, also generates a state of endogenous opioid dependence. Since species-related differences concerning pain biology and addictive behaviors occur between mice and rats, the present study explored whether the coexistence of endogenous opioid analgesia and endogenous opioid dependence also characterizes a homologous rat model. To this aim, CFA-injured Wistar rats were treated with either 3 mg/kg or 10 mg/kg of the opioid receptor inverse agonist naltrexone (NTX) during the pain remission phase and monitored for 60 min for possible withdrawal behaviors. At 3 mg/kg, NTX, besides inducing the reinstatement of mechanical allodynia, also caused a distinct appearance of ptosis, with slight but nonsignificant changes to the occurrence of teeth chatters and rearing. On the other hand, 10 mg/kg of NTX failed to unmask pain sensitization and induced significantly lower levels of ptosis than 3 mg/kg. Such an NTX-related response pattern observed in the rat CFA model seems to differ substantially from the pattern previously described in the mouse CFA model. This supports the knowledge that mice and rats are not identical in terms of pharmacological response and stresses the importance of choosing the appropriate species for preclinical pain research purposes depending on the scientific question being asked.

Automated summary

Studies in mice have shown that constitutive activation of endogenous opioid signaling leads to both endogenous analgesia and opioid dependence. This study aimed to determine if a similar pattern exists in rats. Rats with chronic inflammatory pain were treated with different doses of the opioid receptor inverse agonist naltrexone (NTX) and monitored for withdrawal behaviors. The response to NTX in the rat model was different from the mouse model, suggesting species-related differences in pharmacological response and highlighting the importance of species selection in preclinical pain research.