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Abstract
BackgroundNerve growth factor (NGF) is known to induce inflammation and pain; however its role in opioid-induced tolerance has not been studied. This study investigated the effects of an anti-NGF neutralizing antibody on the development of tolerance following chronic morphine treatment in naïve rats.MethodsFour groups of rats were used in this study; one treated with saline alone, one with 10 mg/kg of morphine, one with 10 μg of anti-NGF and the other with 10 mg/kg of morphine + 10 μg of anti-NGF, twice per day for 5 days. The route of treatment was subcutaneous (S.C.) for morphine and saline, and intraperitoneal (i.p.) for anti-NGF. Response to a noxious thermal stimulus during the course of drug treatment was assessed (Hargreaves’ test). Further, the change in the NGF levels in the lumbar spinal cord was measured by ELISA.ResultsOur results showed that repeated administration of morphine produced an apparent tolerance which was significantly attenuated by co-administration of anti-NGF (P < 0.001). Additionally, the area under the curve (AUC) of the analgesic effect produced by the combination of morphine and anti-NGF was significantly (P < 0.001) greater than for saline controls and chronic morphine treated rats. Moreover, the level of NGF in the spinal cord of chronic morphine treated rats was significantly higher (P < 0.05) than in both the saline control group and the group receiving simultaneous administration of anti-NGF with morphine. These results indicate that anti-NGF has the potential to attenuate morphine-induced tolerance behavior by attenuating the effects of NGF at the spinal level.ConclusionTaken together, our study strongly suggests that the NGF signaling system is a potential novel target for treating opioid-induced tolerance.
Highlights
Nerve growth factor (NGF) is known to induce inflammation and pain; its role in opioid-induced tolerance has not been studied
Repeated morphine treatment alters baseline sensitivity to thermal stimuli As shown in Table 1, before treatment, the baseline paw withdrawal latency in sec (PWL) in all groups ranged from 8.1–9.6 s, and analysis of variance (ANOVA) showed no significant differences between groups (P > 0.05)
The pre-treatment PWL progressively decreased in rats from Mor-Sal, Mor + AntiNGF and Anti-NGF-Sal groups
Summary
Nerve growth factor (NGF) is known to induce inflammation and pain; its role in opioid-induced tolerance has not been studied. This study investigated the effects of an anti-NGF neutralizing antibody on the development of tolerance following chronic morphine treatment in naïve rats. Multiple preclinical and clinical studies have shown that chronic administration of morphine is associated with the development of tolerance [1]. Literature shows that opioid-induced tolerance (OIT), defined as a decreased analgesic response following repeated administration of Cheppudira et al BMC Anesthesiology (2016) 16:73. Exogenous administration of NGF to healthy animals and human subjects induces dose-dependent allodynia and hyperalgesia [5]. We hypothesize that chronic morphine treatment increases spinal cord NGF levels and this contributes to the development of OIT (Fig. 1)
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