Trigeminal transition zone/rostral ventromedial medulla connections and facilitation of orofacial hyperalgesia after masseter inflammation in rats

Abstract

Recent studies have implicated a role for the trigeminal interpolaris/caudalis (Vi/Vc) transition zone in response to orofacial injury. Using combined neuronal tracing and Fos protein immunocytochemistry, we investigated functional connections between the Vi/Vc transition zone and rostral ventromedial medulla (RVM), a key structure in descending pain modulation. Rats were injected with a retrograde tracer, FluoroGold, into the RVM 7 days before injection of an inflammatory agent, complete Freund's adjuvant, into the masseter muscle and perfused at 2 hours postinflammation. A population of neurons in the ventral Vi/Vc overlapping with caudal ventrolateral medulla, and lamina V of the trigeminal subnucleus caudalis (Vc), exhibited FluoroGold/Fos double staining, suggesting the activation of the trigeminal-RVM pathway after inflammation. No double-labeled neurons were found in the dorsal Vi/Vc and laminae I-IV of Vc. Injection of an anterograde tracer, Phaseolus vulgaris leucoagglutinin, into the RVM resulted in labeling profiles overlapped with the region that showed FluoroGold/Fos double labeling, suggesting reciprocal connections between RVM and Vi/Vc. Lesions of Vc with a soma-selective neurotoxin, ibotenic acid, significantly reduced inflammation-induced Fos expression as well as the number of FluoroGold/Fos double-labeled neurons in the ventral Vi/Vc (P<0.05). Compared with control rats, lesions of the RVM (n=6) or Vi/Vc (n=6) with ibotenic acid led to the elimination or attenuation of masseter hyperalgesia/allodynia developed after masseter inflammation (P<0.05-0.01). The present study demonstrates reciprocal connections between the ventral Vi/Vc transition zone and RVM. The Vi/Vc-RVM pathway is activated after orofacial deep tissue injury and plays a critical role in facilitating orofacial hyperalgesia.

Organization of pERK‐immunoreactive cells in trigeminal spinal nucleus caudalis and upper cervical cord following capsaicin injection into oral and craniofacial regions in rats

“…Furthermore, the number of nociceptive neurons that can be analyzed in single-neuron recording studies is limited in any one animal. It is probable that these fiber differences and technical limitation in single-neuron recording may be involved in the distribu- Generally, we observed a pattern of organization of pERK-LI cell expression following capsaicin stimulation of the face that was similar to that reported in previous c-Fos studies Zhou et al, 1999;Takemura et al, 2000;Watanabe et al, 2002;Nomura et al, 2002;Bereiter et al, 2005;Sato et al, 2005;Sugiyo et al, 2005Sugiyo et al, , 2006. However, the distribution of pERK-LI cells was more restricted from the Vi/Vc zone through the Vc/C2 zone compared with previous reports of c-Fospositive neurons Mineta et al, 1995).…”

“…Another approach that has been used is c-Fos labeling to delineate the arrangement of nociceptive neurons in the trigeminal spinal nucleus and upper cervical cord as well as spinal dorsal horn. After noxious stimulation of a variety of orofacial sites, Fos protein like-immunoreactive cells (Fos-LI cells) occur in the trigeminal spinal nucleus interpolaris (Vi) and caudalis (Vc) transition zone (Vi/Vc zone) and the Vc/C2 transition zone Iwata et al, 1998a;Zhou et al, 1999;Takemura et al, 2000;Nomura et al, 2002;Watanabe et al, 2002;Kawabata et al, 2004;Bereiter et al, 2005;Sato et al, 2005;Sugiyo et al, 2005Sugiyo et al, , 2006Shimizu et al, 2006) in a somatotopic arrangement, and their numbers increase as noxious stimulus intensity increases Mineta et al, 1995). However, it has been reported that the c-Fos expression starts at about 30 minutes and peaks about 1 hour after noxious stimulation (Hunt et al, 1987;Tokunaga et al, 1995) in both superficial and deep laminae of the spinal dorsal horn (DH; Bullitt, 1991), so it is very likely that c-Fos expression is not directly correlated with an activation of Vc and upper cervical nociceptive neurons following acute orofacial noxious stimulation.…”

Pain Facilitation and Activity-Dependent Plasticity in Pain Modulatory Circuitry: Role of BDNF-TrkB Signaling and NMDA Receptors

“…Local anesthesia of RVM attenuates mustard oilinduced hyperexcitability of spinal dorsal horn neurons [16] and behavioral hyperalgesia [17]. Lesions of the RVM suppress formalin-induced nocifensive behavior [18], inhibit secondary hyperalgesia produced by topical application of mustard oil [15], and attenuate (secondary) mechanical hyperalgesia after masseter muscle inflammation induced by complete Freund's adjuvant (CFA) [19]. The same phenomenon occurs in models of neuropathic pain.…”

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

“…Following injection of the retrograde tracer Fluorogold into the Vi/Vc transition zone, retrogradely labeled cells were observed in the Vc/C1,2 region (Sato et al ., 2005). After lesions of the bilateral Vc, there is a selective reduction of inflammation-induced Fos-expressing neurons in the ventral Vi/Vc, but not in dorsal or intermediate Vi/Vc, or nucleus tractus solitarius (Sugiyo et al ., 2005). These findings support that trigeminal transition zone activity, particularly the ventral Vi/Vc, is modulated by the activation of the caudal laminated Vc zone.…”