Differential Involvement of Trigeminal Transition Zone and Laminated Subnucleus Caudalis in Orofacial Deep and Cutaneous Hyperalgesia: the Effects of Interleukin-10 and Glial Inhibitors

Abstract

BackgroundIn addition to caudal subnucleus caudalis (Vc) of the spinal trigeminal complex, recent studies indicate that the subnuclei interpolaris/caudalis (Vi/Vc) transition zone plays a unique role in processing deep orofacial nociceptive input. Studies also suggest that glia and inflammatory cytokines contribute to the development of persistent pain. By systematically comparing the effects of microinjection of the antiinflammatory cytokine interleukin (IL)-10 and two glial inhibitors, fluorocitrate and minocycline, we tested the hypothesis that there was a differential involvement of Vi/Vc and caudal Vc structures in deep and cutaneous orofacial pain.ResultsDeep or cutaneous inflammatory hyperalgesia, assessed with von Frey filaments, was induced in rats by injecting complete Freund's adjuvant (CFA) into the masseter muscle or skin overlying the masseter, respectively. A unilateral injection of CFA into the masseter or skin induced ipsilateral hyperalgesia that started at 30 min, peaked at 1 d and lasted for 1-2 weeks. Secondary hyperalgesia on the contralateral site also developed in masseter-, but not skin-inflamed rats. Focal microinjection of IL-10 (0.006-1 ng), fluorocitrate (1 μg), and minocycline (0.1-1 μg) into the ventral Vi/Vc significantly attenuated masseter hyperalgesia bilaterally but without an effect on hyperalgesia after cutaneous inflammation. Injection of the same doses of these agents into the caudal Vc attenuated ipsilateral hyperalgesia after masseter and skin inflammation, but had no effect on contralateral hyperalgesia after masseter inflammation. Injection of CFA into the masseter produced significant increases in N-methyl-D-aspartate (NMDA) receptor NR1 serine 896 phosphorylation and glial fibrillary acidic protein (GFAP) levels, a marker of reactive astrocytes, in Vi/Vc and caudal Vc. In contrast, cutaneous inflammation only produced similar increases in the Vc.ConclusionThese results support the hypothesis that the Vi/Vc transition zone is involved in deep orofacial injury and suggest that glial inhibition and interruption of the cytokine cascade after inflammation may provide pain relief.

Neuropathic ocular pain: an important yet underevaluated feature of dry eye

“…Other untested therapies for dry eye include glial inhibitors, anti-inflammatory cytokines, and/or NMDA receptor inhibitors, all of which have been shown to attenuate facial painmediated via central mechanisms potentially common to those of dry eye. [111][112][113] With many agents available to treat neuropathic pain, research is needed to understand Systemically, there is still controversy on the best management algorithm for patients with neuropathic pain, and this may vary depending on pain severity, underlying pathophysiology (eg, postherpetic neuralgia (PHN), diabetic polyneuropathy), and systemic comorbidities. Our general algorithm for nonocular neuropathic pain includes the use of the novel alpha 2 delta ligand antiepileptics (eg, gabapentin; pregabalin) as first-line agents, serotonin-norepinephrine reuptake inhibitors (eg, duloxetine; venlafaxine) as second-line agents (or as first-line agents in certain patients, such as those with concomitant musculoskeletal pain or with concomitant depression), and tricyclic antidepressants (eg, nortriptyline, amitriptyline) as third-line agents because of their side effects.…”

The Role Of Trigeminal Interpolaris-Caudalis Transition Zone In Persistent Orofacial Pain

“…Pretreatment with glial inhibitors does not block IL-1beta-induced hyperalgesia even with relatively high doses that have been shown to be effective in attenuating hyperalgesia after injury (Wei et al ., 2008; Shimizu et al ., 2009b). Although the glial inhibitor/modulator propentofylline do not block IL-1beta-induced hyperalgesia, propentofylline was able to attenuate hyperalgesia after masseter inflammation (Shimizu et al ., unpublished observations).…”

Tetracyclines and pain

“…Intrathecal injection of lipopolysaccharide (LPS), a toll-like receptor 4 (TLR4) agonist, induces mechanical allodynia in a dose-dependent manner, and this nociceptive sensitisation is inhibited by intrathecal minocycline (Saito et al 2010). Local microinjection of minocycline inhibits thermal hyperalgesia in a model of orofacial pain induced by complete Freund's adjuvant (CFA) injection into the masseter muscle (Shimizu et al 2009). In a model of muscle inflammatory pain in which CFA is injected into the gastrocnemius-soleus muscle, chronic intrathecal minocycline inhibits mechanical allodynia (Chacur et al 2009).…”