Reduction of opioid withdrawal and potentiation of acute opioid analgesia by systemic AV411 (ibudilast).

Morphine-induced glial proinflammatory responses have been documented to contribute to tolerance to opioid analgesia. Here, we examined whether drugs previously shown to suppress glial proinflammatory responses can alter other clinically relevant opioid effects; namely, withdrawal or acute analgesia. AV411 (ibudilast) and minocycline, drugs with distinct mechanisms of action that result in attenuation of glial proinflammatory responses, each reduced naloxone-precipitated withdrawal. Analysis of brain nuclei associated with opioid withdrawal revealed that morphine altered expression of glial activation markers, cytokines, chemokines, and a neurotrophic factor. AV411 attenuated many of these morphine-induced effects. AV411 also protected against spontaneous withdrawal-induced hyperactivity and weight loss recorded across a 12-day timecourse. Notably, in the spontaneous withdrawal study, AV411 treatment was delayed relative to the start of the morphine regimen so to also test whether AV411 could still be effective in the face of established morphine dependence, which it was. AV411 did not simply attenuate all opioid effects, as co-administering AV411 with morphine or oxycodone caused three-to-five-fold increases in acute analgesic potency, as revealed by leftward shifts in the analgesic dose response curves. Timecourse analyses revealed that plasma morphine levels were not altered by AV411, suggestive that potentiated analgesia was not simply due to prolongation of morphine exposure or increased plasma concentrations. These data support and extend similar potentiation of acute opioid analgesia by minocycline, again providing converging lines of evidence of glial involvement. Hence, suppression of glial proinflammatory responses can significantly reduce opioid withdrawal, while improving analgesia.

Transcutaneous electrical nerve stimulation at both high and low frequencies reduces primary hyperalgesia in rats with joint inflammation in a time-dependent manner.

BACKGROUND AND PURPOSE: Clinical studies of transcutaneous electrical nerve stimulation (TENS) have used a variety of outcome measures to assess its effectiveness, with conflicting results. It is possible that TENS is effective on some measures of pain and not on others. The purpose of this study was to test the hypothesis that TENS reduces primary hyperalgesia of the knee induced by joint inflammation. SUBJECTS: Male Sprague-Dawley rats were used in this study. METHODS: Inflammation of the knee joint was induced by intra-articular injection of a mixture of 3% kaolin and 3% carrageenan. Primary hyperalgesia was measured as the compression withdrawal threshold of the knee joint before and after the induction of inflammation (4 hours, 24 hours, and 2 weeks) and after sham TENS treatment, treatment with high-frequency TENS (100 Hz), or treatment with low-frequency TENS (4 Hz). RESULTS: The compression withdrawal threshold was significantly reduced at 4 hours, 24 hours, and 2 weeks after the induction of inflammation. Either high-frequency TENS or low-frequency TENS completely reversed the compression withdrawal threshold when applied at 24 hours or 2 weeks after the induction of inflammation but not when applied at 4 hours after the induction of inflammation. DISCUSSION AND CONCLUSION: These data suggest that TENS inhibits primary hyperalgesia associated with inflammation in a time-dependent manner after inflammation has already developed during both acute and chronic stages.

Characterization of a method for measuring primary hyperalgesia of deep somatic tissue.

UNLABELLED: Measuring primary hyperalgesia from deep somatic tissue (ie, muscle and joint) is difficult in laboratory animals but clinically important. In this study, we modified a newly developed method to measure primary hyperalgesia of muscle in rats and compared this with primary hyperalgesia from the knee. Compression withdrawal thresholds of the gastrocnemius muscle or the knee joint were measured with a device consisting of strain gauges attached to forceps. Compression of the muscle or joint with the forceps results in hind limb withdrawal, and thresholds were measured before and 4 hours after induction of inflammation by 3% carrageenan injected into the gastrocnemius muscle or 3% kaolin-carrageenan injected into the knee joint. Compression thresholds were significantly decreased 4 hours after induction of inflammation in the muscle or knee joint compared with thresholds before inflammation. Surprisingly, in animals with muscle inflammation, compression thresholds were also significantly decreased on the contralateral hind limb. Systemic morphine (5 mg/kg, intraperitoneal) or lidocaine (2%) injected into the inflamed tissue reversed the decreased compression threshold induced by deep tissue inflammation. However, local anesthetic applied to the skin overlying the muscle or knee joint did not affect the decreased threshold. Thus, we report a consistent and convenient method to measure primary hyperalgesia in deep tissues of rats. The measured hyperalgesia originates in the inflamed tissues and has no measurable contribution from skin. PERSPECTIVE: The current method measures primary hyperalgesia directly from injured deep somatic tissues. Thus it is relevant to painful clinical conditions that are aggravated by mechanical pressure at the site of injury. As such, it might serve as a model for basic mechanistic studies as well as drug discovery for musculoskeletal pain syndromes.