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Tolerance to the antinociceptive effects of chronic morphine requires c-Jun N-terminal kinase.

Marcus DJ, Zee M, Hughes A, Yuill MB, Hohmann AG, Mackie K, Guindon J, Morgan DJ - Mol Pain (2015)

Bottom Line: We found that JNK inhibition by SP600125 (3 mg/kg) produces a greater antinociceptive effect than morphine (6 mg/kg) alone in the formalin test.Strikingly, SP600125 (3 mg/kg) pre-treatment prolonged the anti-allodynic effect of morphine by several days (5 and 7 days for mechanical and cold, respectively).Thus, inhibition of JNK signaling pathway, via SP600125, represents an efficacious pharmacological approach to delay tolerance to the antinociceptive effects of chronic morphine in diverse pain models.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology, Penn State College of Medicine, 500 University Drive, Room C2850, Mailcode H187, 17033, Hershey, PA, USA.

ABSTRACT

Background: Morphine and fentanyl are opioid analgesics in wide clinical use that act through the μ-opioid receptor (MOR). However, one limitation of their long-term effectiveness is the development of tolerance. Receptor desensitization has been proposed as a putative mechanism driving tolerance to G protein-coupled receptor (GPCR) agonists. Recent studies have found that tolerance to morphine is mediated by the c-Jun N-terminal Kinase (JNK) signaling pathway. The goal of the present study was to test the hypotheses that: 1) JNK inhibition will be antinociceptive on its own; 2) JNK inhibition will augment morphine antinociception and; 3) JNK mediates chronic tolerance for the antinociceptive effects of morphine using acute (hotplate and tail-flick), inflammatory (10 μl of formalin 2.5%) and chemotherapy (cisplatin 5 mg/kg ip once weekly)-induced neuropathic pain assays.

Results: We found that JNK inhibition by SP600125 (3 mg/kg) produces a greater antinociceptive effect than morphine (6 mg/kg) alone in the formalin test. Moreover, co-administration of morphine (6 mg/kg) with SP600125 (3 mg/kg) produced a sub-additive antinociceptive effect in the formalin test. We also show that pre-treatment with SP600125 (3 or 10 mg/kg), attenuates tolerance to the antinociceptive effects of morphine (10 mg/kg), but not fentanyl (0.3 mg/kg), in the tail-flick and hotplate tests. Pre-treatment with SP600125 also attenuates tolerance to the hypothermic effects of both morphine and fentanyl. We also examined the role of JNK in morphine tolerance in a cisplatin-induced model of neuropathic pain. Interestingly, treatment with SP600125 (3 mg/kg) alone attenuated mechanical and cold allodynia in a chemotherapy-induced pain model using cisplatin. Strikingly, SP600125 (3 mg/kg) pre-treatment prolonged the anti-allodynic effect of morphine by several days (5 and 7 days for mechanical and cold, respectively).

Conclusions: These results demonstrate that JNK signaling plays a crucial role in mediating antinociception as well as chronic tolerance to the antinociceptive effects of morphine in acute, inflammatory, and neuropathic pain states. Thus, inhibition of JNK signaling pathway, via SP600125, represents an efficacious pharmacological approach to delay tolerance to the antinociceptive effects of chronic morphine in diverse pain models.

No MeSH data available.


Related in: MedlinePlus

Schematic representation of different hypotheses/mechanisms involved in the development of tolerance to the antinociceptive effect of fentanyl and morphine. Down-regulation and desensitization of MOR represent two possible biochemical processes that could underlie JNK-mediated morphine tolerance in vivo. The findings of our study and others suggests that tolerance for the antinociceptive effects of morphine is mediated by JNK signaling, possibly through desensitization of MOR, defined for this study as the functional uncoupling of the receptor from its G protein signaling components. In contrast, inhibition of JNK does not alter tolerance for the antinociceptive effects of fentanyl. Tolerance for the antinociceptive effects of fentanyl appears to be mediated by a classic mechanism involving GRK phosphorylation of MOR followed by βarrestin2 recruitment
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Fig7: Schematic representation of different hypotheses/mechanisms involved in the development of tolerance to the antinociceptive effect of fentanyl and morphine. Down-regulation and desensitization of MOR represent two possible biochemical processes that could underlie JNK-mediated morphine tolerance in vivo. The findings of our study and others suggests that tolerance for the antinociceptive effects of morphine is mediated by JNK signaling, possibly through desensitization of MOR, defined for this study as the functional uncoupling of the receptor from its G protein signaling components. In contrast, inhibition of JNK does not alter tolerance for the antinociceptive effects of fentanyl. Tolerance for the antinociceptive effects of fentanyl appears to be mediated by a classic mechanism involving GRK phosphorylation of MOR followed by βarrestin2 recruitment

Mentions: In acute pain tests, chronic tolerance to morphine, a modestly efficacious and weakly internalizing MOR agonist, is mediated primarily by JNK while tolerance to the more efficacious and strongly internalizing opioid, fentanyl is not [4, 15, 21] (Fig. 7). Thus, antinociceptive tolerance for strongly internalizing (e.g., fentanyl) MOR ligands may be mediated by a ‘classical’ GRK/βarrestin mechanism while tolerance for weakly internalizing ligands (e.g., morphine) is likely to be mediated by JNK signaling mechanisms, potentially in a cell-type specific manner [4, 15, 21] (Fig. 7).Fig. 7


Tolerance to the antinociceptive effects of chronic morphine requires c-Jun N-terminal kinase.

Marcus DJ, Zee M, Hughes A, Yuill MB, Hohmann AG, Mackie K, Guindon J, Morgan DJ - Mol Pain (2015)

Schematic representation of different hypotheses/mechanisms involved in the development of tolerance to the antinociceptive effect of fentanyl and morphine. Down-regulation and desensitization of MOR represent two possible biochemical processes that could underlie JNK-mediated morphine tolerance in vivo. The findings of our study and others suggests that tolerance for the antinociceptive effects of morphine is mediated by JNK signaling, possibly through desensitization of MOR, defined for this study as the functional uncoupling of the receptor from its G protein signaling components. In contrast, inhibition of JNK does not alter tolerance for the antinociceptive effects of fentanyl. Tolerance for the antinociceptive effects of fentanyl appears to be mediated by a classic mechanism involving GRK phosphorylation of MOR followed by βarrestin2 recruitment
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4465461&req=5

Fig7: Schematic representation of different hypotheses/mechanisms involved in the development of tolerance to the antinociceptive effect of fentanyl and morphine. Down-regulation and desensitization of MOR represent two possible biochemical processes that could underlie JNK-mediated morphine tolerance in vivo. The findings of our study and others suggests that tolerance for the antinociceptive effects of morphine is mediated by JNK signaling, possibly through desensitization of MOR, defined for this study as the functional uncoupling of the receptor from its G protein signaling components. In contrast, inhibition of JNK does not alter tolerance for the antinociceptive effects of fentanyl. Tolerance for the antinociceptive effects of fentanyl appears to be mediated by a classic mechanism involving GRK phosphorylation of MOR followed by βarrestin2 recruitment
Mentions: In acute pain tests, chronic tolerance to morphine, a modestly efficacious and weakly internalizing MOR agonist, is mediated primarily by JNK while tolerance to the more efficacious and strongly internalizing opioid, fentanyl is not [4, 15, 21] (Fig. 7). Thus, antinociceptive tolerance for strongly internalizing (e.g., fentanyl) MOR ligands may be mediated by a ‘classical’ GRK/βarrestin mechanism while tolerance for weakly internalizing ligands (e.g., morphine) is likely to be mediated by JNK signaling mechanisms, potentially in a cell-type specific manner [4, 15, 21] (Fig. 7).Fig. 7

Bottom Line: We found that JNK inhibition by SP600125 (3 mg/kg) produces a greater antinociceptive effect than morphine (6 mg/kg) alone in the formalin test.Strikingly, SP600125 (3 mg/kg) pre-treatment prolonged the anti-allodynic effect of morphine by several days (5 and 7 days for mechanical and cold, respectively).Thus, inhibition of JNK signaling pathway, via SP600125, represents an efficacious pharmacological approach to delay tolerance to the antinociceptive effects of chronic morphine in diverse pain models.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology, Penn State College of Medicine, 500 University Drive, Room C2850, Mailcode H187, 17033, Hershey, PA, USA.

ABSTRACT

Background: Morphine and fentanyl are opioid analgesics in wide clinical use that act through the μ-opioid receptor (MOR). However, one limitation of their long-term effectiveness is the development of tolerance. Receptor desensitization has been proposed as a putative mechanism driving tolerance to G protein-coupled receptor (GPCR) agonists. Recent studies have found that tolerance to morphine is mediated by the c-Jun N-terminal Kinase (JNK) signaling pathway. The goal of the present study was to test the hypotheses that: 1) JNK inhibition will be antinociceptive on its own; 2) JNK inhibition will augment morphine antinociception and; 3) JNK mediates chronic tolerance for the antinociceptive effects of morphine using acute (hotplate and tail-flick), inflammatory (10 μl of formalin 2.5%) and chemotherapy (cisplatin 5 mg/kg ip once weekly)-induced neuropathic pain assays.

Results: We found that JNK inhibition by SP600125 (3 mg/kg) produces a greater antinociceptive effect than morphine (6 mg/kg) alone in the formalin test. Moreover, co-administration of morphine (6 mg/kg) with SP600125 (3 mg/kg) produced a sub-additive antinociceptive effect in the formalin test. We also show that pre-treatment with SP600125 (3 or 10 mg/kg), attenuates tolerance to the antinociceptive effects of morphine (10 mg/kg), but not fentanyl (0.3 mg/kg), in the tail-flick and hotplate tests. Pre-treatment with SP600125 also attenuates tolerance to the hypothermic effects of both morphine and fentanyl. We also examined the role of JNK in morphine tolerance in a cisplatin-induced model of neuropathic pain. Interestingly, treatment with SP600125 (3 mg/kg) alone attenuated mechanical and cold allodynia in a chemotherapy-induced pain model using cisplatin. Strikingly, SP600125 (3 mg/kg) pre-treatment prolonged the anti-allodynic effect of morphine by several days (5 and 7 days for mechanical and cold, respectively).

Conclusions: These results demonstrate that JNK signaling plays a crucial role in mediating antinociception as well as chronic tolerance to the antinociceptive effects of morphine in acute, inflammatory, and neuropathic pain states. Thus, inhibition of JNK signaling pathway, via SP600125, represents an efficacious pharmacological approach to delay tolerance to the antinociceptive effects of chronic morphine in diverse pain models.

No MeSH data available.


Related in: MedlinePlus