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. Author manuscript; available in PMC: 2017 Jul 16.
Published in final edited form as: Nat Med. 2017 Jan 16;23(2):164–173. doi: 10.1038/nm.4262

Figure 6. Combination therapy of morphine and MNB delivers long-lasting antinociception, without the onset of tolerance, during perioperative and chronic pain states.

Figure 6

(a,d,g,j) Timecourse for (a,g) nociceptive hypersensitivity and (d,j) affective-motivational behaviors following an orthotrauma (tibia fracture and bone pinning), or a peripheral nerve injury (Chronic Constriction Injury, CCI), and the effect of chronic saline (n = 10 for fracture, n = 5 for CCI), 10 mg/kg morphine (n = 10 / injury model), or 10 mg/kg morphine + 10 mg/kg MNB (n = 10 / injury model) treatments. Treatments are first given on PID 7 and re-administered once daily until PID 14, with the exception that the Saline group is administered acute morphine only on PID 7 and PID 14. (b,e,h,k) Antinociceptive tolerance: (left panels) Maximal possible effect (MPE) for morphine antinociception from the first administration (PID 7: +30 min) compared to the last administration (PID 14: +30 min) (Fracture: von Frey, F2, 21 = 2.05, P = 0.0023; 55 °C drop, F2, 21 = 6.084, P = 0.0082. CCI: von Frey, F2, 27 = 13.8, P = 0.0009; Acetone drop, F2, 27 = 5.976, P = 0.0213), and (right panels) the percent change for each subject. (c,f,i,l) OIH: (left panels) Percent change in the pre-morphine baseline nociceptive behaviors prior to the first administration (PID 7: BL) compared to just to the last (PID 14: BL) (Fracture: von Frey, F2, 22 = 4.253, P = 0.0274; 55 °C drop, F2, 21 = 5.347, P = 0.0133. CCI: von Frey, F2, 27 = 0.05814, P = 0.9436; Acetone drop, F2, 27 = 0.4272, P = 0.6567), and (right panels) the percent change for each subject. (m,n) Schematic detailing the influence of opioid-induced nociceptor maladaptive potentiation over CNS analgesic circuits to initiate tolerance and OIH. Conditional MOR deletion or MNB blockade of MOR signaling in nociceptors abrogates this potentiation, thereby maintaining opioid analgesic efficacy and reducing OIH. Two-way ANOVA + Bonferroni (for panels c,f,i,l two separate ANOVAs were run for Pre-injury vs. PID7, and PID7 vs. PID14). Student’s t Test, two-tailed (right panels of b,c,e,f,h,i,k,l). ★ P < 0.05. Error bars are mean ± SEM. Overlaid points are individual animal scores. PID = post-injury day.