Evidence of Central and Peripheral Sensitization in a Rat Model of Narcotic Bowel-Like Syndrome

Opioid-induced hypernociception is associated with hyperexcitability and altered tetrodotoxin-resistant Na+ channel function of dorsal root ganglia

“…In addition to tolerance development to the analgesic effects of opiates being a major impediment to pain therapy, chronic opiate-induced hypernociception has become a critical problem. This phenomenon of opiate-induced hypernociception is also demonstrated in several experimental animal models such as thermal and tactile nociception in mice (56) as well as in a rat model of narcotic bowel syndrome (1). Rats develop visceral hyperalgesia to colorectal distension after day 6 of morphine administration (1).…”

“…Morphine can activate spinal microglia (51, 52) and may cause hyperexcitability through inflammatory mediators released from microglia. Indeed, in a rat model of narcotic bowel syndrome, inhibition of microglia by minocycline reduced the morphine-induced visceral hyperalgesia (1). Therefore, the involvement of spinal glial cells on chronic morphine-induced hyperexcitability and altered TTX-R Na ϩ biophysics in DRGs is an attractive area for further studies.…”

“…This phenomenon of opiate-induced hypernociception is also demonstrated in several experimental animal models such as thermal and tactile nociception in mice (56) as well as in a rat model of narcotic bowel syndrome (1). Rats develop visceral hyperalgesia to colorectal distension after day 6 of morphine administration (1). In mice, chronic morphine administration produced thermal as well as tactile hypersensitivity 7 days after morphine pellet implantation (56).…”

“…The mechanisms involved in the development of opiate-induced hypernociception are not clearly known, but it appears to be a multifactorial neurobiological process, including 1) primary afferent sensitization, 2) altered production, release, and reuptake of excitatory neurotransmitters, 3) second-order neuron sensitization to excitatory neurotransmitters, and 4) increased descending facilitation due to rostral ventromedial medullary neuroplastic changes leading to enhanced primary afferent neurotransmitter release and pain (6,23). Probable changes in the first-order neurons that carry pain signals from visceral organs could also be involved in amplification of the pain signals, since recent reports show evidence for both central and peripheral sensitization mechanisms causing narcotic bowel syndrome (1), and also changes at the dorsal root ganglion (DRG) level with respect to transient receptor potential vanilloid 1 (TRPV1) channels were suggested to be involved in thermal and tactile hypersensitivity. Therefore, it is highly likely that any opioid-induced change in the excitability status of the sensory neurons could contribute to opioid-induced hypernociception.…”

Neuroprotection by Minocycline Caused by Direct and Specific Scavenging of Peroxynitrite

“…Its beneficial in vivo activities have been suggested to be mainly based on its capacity to dampen glia activation and to reduce the tissue concentration of inflammatory mediators contributing to the degeneration process (11,(15)(16)(17)(18)(19). Accordingly, alterations of cell function by the antibiotic are best described for brain macrophages and microglial cells (20,21). The majority of studies describe a reduced up-regulation of inflammatory components, such as surface markers, cytokines, or pro-inflammatory enzymes (22,23).…”