Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 18 (1), 1320-6

Morphine Induces Hyperalgesia Without Involvement of μ-Opioid Receptor or morphine-3-glucuronide

Affiliations

Morphine Induces Hyperalgesia Without Involvement of μ-Opioid Receptor or morphine-3-glucuronide

Maarten Swartjes et al. Mol Med.

Abstract

Opioid-induced hyperalgesia (OIH) is a paradoxical increase in pain perception that may manifest during opioid treatment. For morphine, the metabolite morphine-3-glucuronide (M3G) is commonly believed to underlie this phenomenon. Here, in three separate studies, we empirically assess the role of M3G in morphine-induced hyperalgesia. In the first study, CD-1 mice injected with morphine (15 mg/kg subcutaneously) after pretreatment with the opioid receptor antagonist naltrexone (NTX) (15 mg/kg) showed tail withdrawal latency reductions indicative of hyperalgesia (2.5 ± 0.1 s at t = 30 min, P < 0.001 versus baseline). In these mice, the morphine/M3G concentration ratios versus effect showed a negative correlation (r(p) = -0.65, P < 0.001), indicating that higher morphine relative to M3G concentrations are associated with increased OIH. In the second study, similar hyperalgesic responses were observed in mice lacking the multidrug resistance protein 3 (MRP3) transporter protein (Mrp3(-/-) mice) in the liver and their wild-type controls (FVB mice; latency reductions: 3.1 ± 0.2 s at t = 30 min, P < 0.001 versus within-strain baseline). In the final study, the pharmacokinetics of morphine and M3G were measured in Mrp3(-/-) and FVB mice. Mrp3(-/-) mice displayed a significantly reduced capacity to export M3G into the systemic circulation, with plasma M3G concentrations just 7% of those observed in FVB controls. The data confirm previous literature that morphine causes hyperalgesia in the absence of opioid receptor activation but also indicate that this hyperalgesia may occur without a significant contribution of hepatic M3G. The relevance of these data to humans has yet to be demonstrated.

Figures

Figure 1
Figure 1
Design (A) and pharmacodynamic results of study 1 (B, C): effect of saline and NTX pretreatment on morphine-(MOR) or saline-induced changes in TWL in CD-1 mice. (A) Timing of TWL measurements and drug injections. (B) Saline pretreatment caused morphine-induced analgesia. Saline/MOR versus NTX/saline: P < 0.001; *P < 0.001 versus baseline. (C) NTX pretreatment caused morphine-induced hyperalgesia. The combination NTX/saline had no effect on the measured latencies. NTX/MOR versus NTX/saline: P < 0.001; *P < 0.001 versus baseline. Values are means ± SEM.
Figure 2
Figure 2
Morphine and M3G pharmacokinetics and pharmacodynamics in CD-1 mice (study 1). (A) Mean morphine plasma concentrations versus time in mice treated with saline followed by morphine (saline/MOR) and mice treated with NTX followed by morphine (NTX/MOR). (B) Mean M3G plasma concentrations versus time in mice treated with saline followed by morphine (saline/MOR) and mice treated with NTX followed by morphine (NTX/MOR). (C) Individual morphine (open circle) and M3G (closed circle) plasma concentrations after saline pretreatment versus effect (TWL). To guide the eye, a sigmoid function is fitted through the two data sets. (D) Individual morphine (open circle) and M3G (closed circle) plasma concentrations after NTX pretreatment versus effect (TWL). To guide the eye, an exponential function is fitted through the two data sets. (E) The ratio of the plasma concentrations morphine and M3G (morphine/M3G) versus TWL for animals treated with saline/MOR. There is a clear positive correlation for ratios <0.03 ( rp = 0.72). At ratios >0.03, no further increase in TWL was observed because of the preset cutoff value of 30 s. The line through the data is a sigmoid fitted to the whole data set (R2 = 0.94). Two outliers (open squares) were not taken into account in the analysis. Each data point is one morphine/M3G measurement obtained in one mouse. PK samples were obtained at t = 30, 60, 90 and 120 min after morphine injection. (F) The ratio of the plasma concentrations morphine and M3G (morphine/M3G) versus TWL for animals treated with NTX/MOR. A negative correlation was present with rp = −0.65. Each data point is one morphine/M3G measurement obtained in one mouse. PK samples were obtained at t = 30, 60, 90 and 120 min after morphine injection.
Figure 3
Figure 3
Pharmacodynamic results of study 2. Effect of NTX pretreatment on morphine or saline induced changes in TWL in FVB and Mrp3−/− mice. NTX pretreatment caused morphine-induced hyperalgesia in both genotypes. The combination NTX/saline had no effect on the measured latencies. Treatment effect (NTX/MOR versus NTX/saline) is shown in FVB mice (P < 0.001) and Mrp3−/− mice (P < 0.001). Strain comparison, P = 0.10. *P < 0.001 versus baseline. Values are means ± SEM. t = 0 is the time of the morphine or saline subcutaneous injection.
Figure 4
Figure 4
Pharmacokinetic results of study 3. (A) Morphine and M3G plasma concentration in FVB and Mrp3−/− mice. (B) The 24-h morphine and M3G excretion in FVB and Mrp3−/− mice. Values are means ± SEM. *P < 0.05 versus FVB mice.

Similar articles

See all similar articles

Cited by 3 articles

Feedback