Pituitary adenylate cyclase-activating polypeptide type 1 receptor signaling evokes long-lasting nociceptive behaviors through the activation of spinal astrocytes in mice

Ohnou, Tetsuya; Yokai, Masafumi; Kurihara, Takashi; Hasegawa-Moriyama, Maiko; Shimizu, Takao; Inoue, Kazuhiko; Kambe, Yuki; Kanmura, Yuichi; Miyata, Atsuro

doi:10.1016/j.jphs.2016.01.008

Cited by 22 publications

(51 citation statements)

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“…Exposure of PACAP (0.0001 ~ 10 nM) or Max (0.1 ~ 10 nM) dose-dependently decreased glycogen amount ( Figure 3A, B ), but VIP failed to decrease the glycogen amount even at the concentration of 10 nM ( Figure 3C ), suggesting that PAC1 receptor is primarily involved in the glycogenolysis. Interestingly, this pharmacological characteristic of glycogenolysis was very similar to that of the PACAP-induced nociceptive behaviors in mice reported previously ( Ohnou et al, 2016; Yokai et al, 2016 ). This PACAP-induced glycogenolysis was completely abolished by the DAB (1 mM) ( Figure 3D ), indicating that the glycogenolysis by PACAP would be mediated by PYGB.…”

Section: Resultssupporting

confidence: 87%

“…Previously, we showed that i.t. injection of Max or PACAP induced rapid and prolonged upregulation of spinal GFAP expression level in parallel with the aversive behaviors and long-lasting mechanical allodynia, and simultaneous application of L-α-aminoadipate, an astrocyte toxin, with Max or PACAP markedly suppressed the aversive behaviors and the mechanical allodynia ( Ohnou et al, 2016; Yokai et al, 2016 ). Interestingly, it is suggested that glycogen metabolism is associated with maturation of astrocytes, in which the expressional levels of GFAP and glycogen synthase or phosphorylase are increased in parallel ( Brunet et al, 2010 ).…”

Section: Discussionmentioning

confidence: 97%

“…It may be worth noting our previous data here that i.t. injection of the PKA inhibitor, Rp-8-Br-cAMPS, could ameliorate the PACAP-induced aversive behaviors ( Ohnou et al, 2016 ). Currently it may be difficult to precisely reconcile with the present observation that the PKA inhibitor failed to prevent PACAP-evoked glycogenolysis in the spinal astrocytes, but we could speculate that neuronal PKA signaling would also contribute to the expression of the pain behaviors.…”

Section: Discussionmentioning

confidence: 99%

“…injection of PACAP or a PAC1 receptor specific agonist, maxadilan (Max) ( Moro and Lerner, 1997 ), induced spontaneous aversive behaviors, such as licking, biting, and scratching directed toward the caudal part of the body for more than 30 min ( Shimizu et al, 2004; Ohnou et al, 2016 ), and the aversive behaviors were followed by a induction of the mechanical allodynia, which lasted for more than 84 days ( Yokai et al, 2016 ). However, vasoactive intestinal polypeptide (VIP), which share VIP/PACAP (VPAC) 1 or VPAC2 receptors with PACAP, failed to induce these nociceptive behaviors ( Ohnou et al, 2016; Yokai et al, 2016 ). Co-treatment of a PAC1 receptor antagonist, max.d.4 with PACAP, almost completely inhibited the induction of both aversive behaviors and the mechanical allodynia ( Ohnou et al, 2016; Yokai et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

“…However, vasoactive intestinal polypeptide (VIP), which share VIP/PACAP (VPAC) 1 or VPAC2 receptors with PACAP, failed to induce these nociceptive behaviors ( Ohnou et al, 2016; Yokai et al, 2016 ). Co-treatment of a PAC1 receptor antagonist, max.d.4 with PACAP, almost completely inhibited the induction of both aversive behaviors and the mechanical allodynia ( Ohnou et al, 2016; Yokai et al, 2016 ). These results suggested critical role of PAC1 receptor in nociceptive transmission.…”

Section: Introductionmentioning

confidence: 99%

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Spinal astrocyte-neuron lactate shuttle contributes to the PACAP/PAC1 receptor-induced nociceptive behaviors

Kambe

Yokai

Takasaki

et al. 2018

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21 lactate shuttle, protein kinase C, monocarboxylate transporter, glycogenolysis 22 23 Abbreviations used: artificial cerebrospinal fluid (ACSF), adenylate cyclase (AC), 24 astrocyte-neuron lactate shuttle (ANLS), central nervous system (CNS), glial fibrillary 25 acidic protein (GFAP), intrathecal (i.t.), maxadilan (Max), monocarboxylate transporter 26 (MCT), pituitary adenylate cyclase-activating polypeptide (PACAP), protein kinase A 27 (PKA), protein kinase C (PKC), phorbol 12-myristate 13-acetate (PMA), glycogen 28 phosphorylase (PYGB), vasoactive intestinal polypeptide (VIP) 29 30 3 Abstract Previously, we showed that spinal pituitary adenylate cyclase-activating 31 polypeptide (PACAP)/PAC1 receptor signaling triggers long-lasting pain behaviors 32 through astroglial activation. Since astrocyte-neuron lactate shuttle (ANLS) could be 33 essential for long-term synaptic facilitation, we aimed to elucidate a possible 34 involvement of spinal ANLS in the development of the PACAP/PAC1 receptor-induced 35 pain behaviors. A single intrathecal administration of PACAP induced short-term 36 spontaneous aversive behaviors, followed by long-lasting mechanical allodynia. These 37 pain behaviors were inhibited by DAB, an inhibitor of glycogenolysis, and this 38 inhibition was reversed by simultaneous L-lactate application. In the cultured spinal 39 astrocytes, the PACAP-evoked glycogenolysis and lactate secretion were inhibited by a 40 protein kinase C (PKC) inhibitor, and the PKC inhibitor attenuated the PACAP-induced 41 pain behaviors. Finally, an inhibitor for the monocarboxylate transporters blocked the 42 lactate secretion from the spinal astrocytes and inhibited the PACAP-induced pain 43 behaviors. These results suggested that PAC1 receptor-PKC-ANLS signaling is 44 involved in the PACAP-induced pain behaviors.45 46 64 5 neurotransmitters evoke the ANLS activation during any forms of neuronal plasticity. 65 66Pituitary adenylate cyclase-activating polypeptide (PACAP) was originally isolated 67 from ovine hypothalamic extracts based on its ability to stimulate adenylate cyclase in 68 rat anterior pituitary cell cultures (Miyata et al., 1989; Miyata et al., 1990). In normal 69 state, PACAP specific receptor, PAC1 receptor, is particularly abundant in central 70 nervous system (CNS) including spinal dorsal horn (Dickinson et al., 1999; Jongsma et 71 al., 2000; Sakashita et al., 2001; Vaudry et al., 2009; Yokai et al., 2016), where 72 PACAP-immunoreactive fibers are also considerably localized (Moller et al., 1993; 73 Dun et al., 1996a; Dun et al., 1996b; Narita et al., 1996), and PACAP 74 mRNA/immunoreactivity in rat dorsal root ganglia is markedly upregulated in 75 peripheral nerve injury or inflammation (Zhang et al., 1995; Zhang et al., 1998; 76 Jongsma et al., 2003; Mabuchi et al., 2004). These observations coupled with other 77 lines of evidence propose that PACAP/PAC1 receptor system could play an important 78 role in the modulation of spinal nociceptive transmission.79 80 We have previously demonstrated in mice t...

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Section: Resultssupporting

confidence: 87%