Potential Involvement of μ-Opioid Receptor Dysregulation on the Reduced Antinociception of Morphine in the Inflammatory Pain State in Mice

Abstract

Abstract. The antinociceptive effect of morphine in the inflammatory pain state was described in the von Frey filament test using the complete Freund's adjuvant (CFA)-induced mouse inflammatory pain model. After an i.pl. injection of CFA, mechanical allodynia was observed in the ipsilateral paw. The antinociceptive effect of morphine injected s.c. and i.t. against mechanical allodynia was reduced bilaterally at 1 day and 4 days after the CFA pretreatment. The expression level of mRNA for m-opioid receptors at 1 day after the CFA pretreatment was reduced bilaterally in the lumbar spinal cord and dorsal root ganglion (DRG). In contrast, the protein level of m-opioid receptors at 1 day after CFA pretreatment was decreased in the ipsilateral side in the DRG but not the lumbar spinal cord. Single or repeated i.t. pretreatment with the protein kinase Ca (PKCa) inhibitor Ro-32-0432 completely restored the reduced morphine antinociception in the contralateral paw but only partially restored it in the ipsilateral paw in the inflammatory pain state. In conclusion, reduced morphine antinociception against mechanical allodynia in the inflammatory pain state is mainly mediated via a decrease in m-opioid receptors in the ipsilateral side and via the desensitization of m-opioid receptors in the contralateral side by PKCa-induced phosphorylation.

Treatment with Adenosine Receptor Agonist Ameliorates Pain Induced by Acute and Chronic Inflammation

“…This model differs from neuropathic pain because the hyperalgesia is deeply associated with inflammation; furthermore, there is no time for healing of the pathologic tissues. CFA-induced behavioral changes are usually observed in animals after 3 days (early phase); then they typically continue for at least 3 weeks (Ohsawa et al, 2000;Hong et al, 2009;Aoki et al, 2014b). In the present study, strong hypersensitivity to heat and mechanical responses were characterized by a reduction in paw withdrawal latencies between day 3 and day 7.…”

Morphine Antinociception Restored by Use of Methadone in the Morphine-Resistant Inflammatory Pain State

“…However, in a clinical study, morphine was found to be less effective against inflammatory pain (Lillesø et al, 2000). We previously found that the antinociceptive effect of morphine was markedly suppressed against mechanical allodynia in the inflammatory pain state (Aoki et al, 2014b). In the present study, we further characterized the antinociceptive effect of narcotic analgesics, including morphine, against thermal hyperalgesia in the inflammatory pain state, and found a special effect of methadone in restoring suppressed morphine antinociception in the inflammatory pain state.…”

“…We previously determined the antinociceptive effect of morphine against mechanical allodynia in the CFA-induced inflammatory pain state in mice using the von Frey filament test (Aoki et al, 2014b). In that study, the antinociceptive effect of morphine against mechanical allodynia was bilaterally suppressed at 1 and 4 days after CFA treatment.…”

“…To produce the inflammatory pain model, mice underwent i.pl. injection of 50 µL of CFA (Sigma-Aldrich, St. Louis, MO) in the left hind paw using a syringe with a 26-gauge needle (Aoki et al, 2014a;Aoki et al, 2014b). Control mice underwent i.pl.…”

“…The purified total RNA was quantified using a spectrophotometer at A260. RT-PCR amplification was performed using the SuperScript One Step RT-PCR system Platinum version (Life Technologies, Carlsbad, CA) (Aoki et al, 2014b). The synthetic forward and reverse primers for the µ-opioid receptor were 5'-CAG CCA GCA TTC AGA ACC ATG G-3' and 5'-ATG GTG CAG AGG GTG AAG ATA CTG G-3', respectively.…”