Attenuation of Morphine Tolerance, Withdrawal-Induced Hyperalgesia, and Associated Spinal Inflammatory Immune Responses by Propentofylline in Rats

Abstract

The activation of glial cells and enhanced proinflammatory cytokine expression at the spinal cord has been implicated in the development of morphine tolerance, and morphine withdrawal-induced hyperalgesia. The present study investigated the effect of propentofylline, a glial modulator, on the expression of analgesic tolerance and withdrawal-induced hyperalgesia in chronic morphine-treated rats. Chronic morphine administration through repeated subcutaneous injection induced glial activation and enhanced proinflammatory cytokine levels at the lumbar spinal cord. Moreover, glial activation and enhanced proinflammatory cytokine levels exhibited a temporal correlation with the expression of morphine tolerance and hyperalgesia. Consistently, propentofylline attenuated the development of hyperalgesia and the expression of spinal analgesic tolerance to morphine. The administration of propentofylline during the induction of morphine tolerance also attenuated glial activation and proinflammatory cytokines at the L5 lumbar spinal cord. These results further support the hypothesis that spinal glia and proinflammatory cytokines contribute to the mechanisms of morphine tolerance and associated abnormal pain sensitivity.

Direct Evidence of Astrocytic Modulation in the Development of Rewarding Effects Induced by Drugs of Abuse

“…PPF is known to modulate glial activity under pathological condition (Raghavendra et al, 2004). The mechanism of glial modulation by PPF under pathological condition could be due to its inhibitory action of phosphodiesterase enzymes and subsequent augmentation of cAMP signaling (Schubert et al, 1997).…”

“…On the other hand, MRP (10 mM), but not METH (10 mM) failed to induce the activation of astrocytes in mouse-purified cortical astrocytes. In the present study, we used mouse cortical neuron/glia cocultures to confirm the effect of PPF, which is known to modulate glial activity under pathological conditions (Sweitzer et al, 2001;Raghavendra et al, 2004) in the activation of astrocytes induced by METH and MRP. The activation of astrocytes induced by either METH or MRP was dramatically diminished by treatment with PPF (Figure 1a and b).…”

The impact of morphine after a spinal cord injury

“…Pro-inflammatory cytokines, including interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), are significantly upregulated 1, 3, and 6 hrs after a contusion injury, returning to background levels 1-2 days after injury [35,36]. Morphine appears to further increase pro-inflammatory cytokine levels by activating μ-receptors on spinal glial cells [37,38,39,40]. An increased concentration of pro-inflammatory cytokines may be significant at two levels.…”

“…Subjects treated with 20 mg/kg of morphine also displayed significantly higher vocalization thresholds than those treated with 5 mg/kg (p < 0.05). Trend analyses revealed a significant quadratic relation between dose and surgery on shock thresholds required to elicit vocalization (F (1,40) = 4.13, p < 0.05). Contused rats required significantly more morphine to achieve levels of antinociception comparable to sham controls when vocalization thresholds to incremented shock were assessed.…”

Spinal sample showing p-JNK and P38 associated with the pain signaling transduction of glial cell in neuropathic pain

“…1 Both microglia and astrocytes are activated in the spinal cord after nerve injury. 2 Glial cells not only act as various receptors of neurotransmitters, but also can produce many inflammatory mediators such as interleukin-1β, interleukin-6, tumor necrosis factor-α and prostaglandin E2 that lead to painful sensitization. 3 Spinal microglia is important for the occurrence of neuropathic pain.…”