Molecular Depletion of Descending Serotonin Unmasks Its Novel Facilitatory Role in the Development of Persistent Pain

Abstract

Recent studies indicate that persistent pain after tissue or nerve injury is accompanied by an enhanced net descending facilitatory drive that contributes to an amplification and spread of pain. Although 5-HT-containing neurons in the rostral ventromedial medulla (RVM) provide the major descending serotonergic projection to the spinal cord, it is not clear whether the neurotransmitter 5-HT itself released from RVM-spinal neurons contributes to descending pain modulation. In the present study, we determined the role of the descending 5-HT in rat nocifensive behaviors after persistent pain by selectively depleting functional phenotypes of 5-HT in RVM neurons with regional shRNA interference (RNAi) of tryptophan hydroxylase-2 (Tph-2), the rate-limiting enzyme in the synthesis of neuronal 5-HT. Compared to negative control shRNA, Tph-2 shRNA induced significantly prolonged downregulation of Tph-2 in the RVM and 5-HT in spinal dorsal horn. The 5-HT-depleted rats showed normal pain sensitivity in responses to acute noxious stimulation. However, the same RNAi treatment attenuated formalin-induced spontaneous nocifensive responses and tissue or nerve injury-induced allodynia and hyperalgesia. Furthermore, in control shRNA-treated animals, intra-RVM microinjection of brain-derived neurotrophic factor produced a reversible hyperalgesia, which was completely prevented by Tph-2 RNAi pretreatment. Descending inhibition induced by intra-RVM electrical stimulation, but not microinjection of the -or -opioid receptor agonists in control shRNA-treated animals was eliminated in 5-HT-depleted rats. These results indicate that the descending 5-HT from the RVM is an important contributor to pain facilitation during the development of persistent pain, and may not mediate opioid-induced descending inhibition in acute pain.

Effects of Adjuvant Analgesics on Cerebral Ischemia-Induced Mechanical Allodynia

“…[24][25][26] By contrast, pro-inflammatory and anti-inflammatory cytokines, such as interleukin-1, play crucial roles in the establishment and maintenance of neuropathic pain. 27) Tricyclic antidepressants reportedly inhibited the release of interleukin-1 in mixed glial and microglial cell cultures from rats.…”

Central Sensitization and Descending Facilitation in Chronic Pain State

“…www.intechopen.com Therefore, it is concluded that 5-HT derived from descending fibers from the RVM activated spinal/trigeminal dorsal horn neurons via 5-HT3 receptors and facilitated pain behavior (Okamoto et al, 2005b). Recently, Wei et al (2010) showed the essential role of 5-HT in this system in pathological pain conditions by selectively blocking 5-HT production in the RVM. As for 5-HT2A receptors, we demonstrated that this receptor subtype is involved in the suppression of nociceptive processing and behavior using the deep craniofacial pain model (Okamoto et al, 2007).…”

Central Sensitization: Clinical Implications for Chronic Head and Neck Pain

“…The resulting depression, anxiety, sleep fragmentation, allodynia, and hyperalgesia characterize a number of chronic pain disorders. [2][3][4][5][6][7][8][9][10][11][12][13] At least two etiological pathways are posited for central sensitization. The first is chronification of nociceptive pain; and involves neuroplastic changes, and peripheral sensitization as precursors to central sensitization and the resulting clinical pain.…”

“…[13] Many of the drugs that we use to address central sensitization will have a beneficial effect on the ability of the patient to cope with the pain, as well as to diminish the central sensitization itself. [1,2,8,9,13,41,45] Drugs used to address the effects of central sensitization:…”

“…As such, PENS is one of our few cost-effective, non-invasive, low co-morbidity options for the treatment of central sensitization itself, as opposed to responding to the deleterious effects of CS. [1,2,5,6,[8][9][10][12][13][14][15][20][21][22][23][25][26][27][28][42][43][44]53,55] The other broad category of non-pharmaceutical CS intervention encompasses manual therapy, virtual reality, improving stress tolerance, and transcutaneous electric nerve stimulation. These can be thought of as addressing the functional deficits created by the CS.…”