TABLE 2.
Clinically relevant efficacy of opioids is improved in animal models by inhibition of glial activation or proinflammatory cytokine actions:
| Model | Direction of effect | Intervention |
|---|---|---|
| Opioid induced acute analgesia | enhanced | minocycline28, 34, ibudilast (AV411)31, IL-1032, IL-1ra28, 32, 36, IL-1 signaling KOs36, IL-ra over-expressing transgenics36, classic TLR4 antagonists45, (+)-naloxone45, (-)- naloxone45, ultra-low (-)-opioid antagonists 92, sTNFR28, anti-IL-628, p38 MAPK inhibitor28 |
| Opioid induced analgesia for neuropathic pain | enhanced | propentofylline (SLC022)93, pentoxifylline93 IL-1ra + TNF soluble receptors + anti-IL694 |
| Morphine analgesic tolerance | suppressed | ibudilast (AV411)64, IL-1032, IL-1ra32, fluorocitrate95, minocycline35, pentoxifylline81, (+)-naloxone45, propentofylline (SLC022)33, IL-1 signaling KOs36, IL-ra overexpressing transgenics36, IL-10 + IL-1ra28, IL-1 converting enzyme inhibitor + IL1ra28 |
| Morphine withdrawal-induced pain enhancement | suppressed | IL-1032, IL-1ra32, propentofylline (SLC022)33, (+)-naloxone45, IL-10 + IL-1ra28, IL-1 converting enzyme inhibitor + IL1ra28 |
| Morphine withdrawal-induced pain enhancement in neuropathic rats | suppressed | IL-1ra + TNF soluble receptors + anti-IL694 |
| Precipitated opioid withdrawal behaviors | suppressed | ibudilast (AV411)31, (+)-naloxone45, minocycline31 |
| Spontaneous opioid withdrawal behaviors | suppressed | ibudilast (AV411)31 |
| Morphine induced respiratory depression | suppressed | minocycline34 |
| Morphine induced dopamine release from brain “reward” area (nuc. Accumbens) | suppressed | (+)-naloxone, ibudilast (AV411)96 |
| Morphine induced conditioned place preference | suppressed | minocycline34, propentofylline (SLC022)97 |
| Morphine induced glial activation (IHC) | suppressed | ibudilast (AV411)31, pentoxifylline98, propentofylline (SLC022)99, fluorocitrate95 minocycline74 |
| Morphine induced proinflammatory cytokines & chemokines | suppressed | propentofylline (SLC022)99, (+)-naloxone19, ibudilast (AV411)31 |
Abbreviations: anti-IL6: neutralizing antibodies against interleukin-6, IL-1ra: interleukin-1 receptor antagonist, KOs: knock out mice, TLR4: toll like receptor 4, sTNFR: soluble TNF receptor, IL-10: interleukin-10.