Role of Pituitary Adenylate-Cyclase Activating Polypeptide and Tac1 gene derived tachykinins in sensory, motor and vascular functions under normal and neuropathic conditions

Abstract

a b s t r a c tPituitary Adenylate-Cyclase Activating Polypeptide (PACAP) and Tac1 gene-encoded tachykinins (substance P: SP, neurokinin A: NKA) are expressed in capsaicin-sensitive nerves, but their role in nociception, inflammation and vasoregulation is unclear. Therefore, we investigated the function of these neuropeptides and the NK 1 tachykinin receptor (from Tacr1 gene) in the partial sciatic nerve ligationinduced traumatic mononeuropathy model using gene deficient (PACAP −/− , Tac1 −/− , and Tacr1 −/− ) mice. Mechanonociceptive threshold of the paw was measured with dynamic plantar aesthesiometry, motor coordination with Rota-Rod and cutaneous microcirculation with laser Doppler imaging. Neurogenic vasodilation was evoked by mustard oil stimulating sensory nerves. In wildtype mice 30-40% mechanical hyperalgesia developed one week after nerve ligation, which was not altered in Tac1−/− and Tacr1mice, but was absent in PACAP −/− animals. Motor coordination of the PACAP −/− and Tac1 −/− groups was significantly worse both before and after nerve ligation compared to their wildtypes, but it did not change in Tacr1−/− mice. Basal postoperative microcirculation on the plantar skin of PACAP −/− mice did not differ from the wildtypes, but was significantly lower in Tac1 −/− and Tacr1 −/− ones. In contrast, mustard oil-induced neurogenic vasodilation was significantly smaller in PACAP −/− mice, but not in Tacr1 −/− and Tac1 −/− animals. Both PACAP and SP/NKA, but not NK 1 receptors participate in normal motor coordination. Tachykinins maintain basal cutaneous microcirculation. PACAP is a crucial mediator of neuropathic mechanical hyperalgesia and neurogenic vasodilation. Therefore identifying its target and developing selective, potent antagonists, might open promising new perspectives for the treatment of neuropathic pain and vascular complications.

Induction of Migraine-Like Photophobic Behavior in Mice by Both Peripheral and Central CGRP Mechanisms

“…The efficacy of triptans to attenuate both central (Kaiser et al, 2012) and peripheral CGRP-induced light aversion and motility in mice is consistent with the ability of triptans to reduce CGRPinduced migraine in humans (Asghar et al, 2011). Triptans are a family of antimigraine drugs that activate 5-HT1B/D receptors that induce vasoconstriction and inhibit the release of CGRP and other neuropeptides from nociceptors (Loder, 2010), including possibly inhibition of CGRP release by trigeminal afferents in this study.…”

“…Triptans are a family of antimigraine drugs that activate 5-HT1B/D receptors that induce vasoconstriction and inhibit the release of CGRP and other neuropeptides from nociceptors (Loder, 2010), including possibly inhibition of CGRP release by trigeminal afferents in this study. Despite being studied for Ͼ20 years, the sites of action of triptans remain controversial (Ahn and Basbaum, 2005), but the similar efficacy of various triptans regardless of their brain penetrance supports the importance of a peripheral site of action unless there is blood-brain barrier breakdown, which has yet to be demonstrated (Edvinsson and Tfelt-Hansen, 2008). In addition, the ability of sumatriptan to attenuate the effects of CGRP on both light aversion and motility suggests that these responses may be mediated by overlapping mechanisms.…”

Decreased MicroRNA-125a-3p Contributes to Upregulation of p38 MAPK in Rat Trigeminal Ganglions with Orofacial Inflammatory Pain

“…Previous reports have indicated miR-103 and miR-1a-3p modulate neuropathic or cancer pain through Cav1.2 calcium channel and clcn3, respectively [11], [28]. In the present study, the predicted target genes of miR-23a*, -24-2*, -26a, -92a, -125a-3p, -183, and -299, including NMDA, MAPK and Tac were found to be involved in neuropathic, inflammatory pain, or other states of pain [26], [32]–[34]. Furthermore, GO analysis indicated miR-125a-3p was involved in some processes of pain transduction including transmission of nerve impulse, synaptic transmission, regulation of action potential in neuron, regulation of inflammatory response and regulation of gene expression, which reminds us to pay more attention to it.…”

Differential Regulatory Role of Pituitary Adenylate Cyclase–Activating Polypeptide in the Serum‐Transfer Arthritis Model

“…PACAP has a potent vasodilatory effect through the PAC 1 receptor and facilitates plasma leakage, edema formation, and leukocyte migration (). We have also shown that PACAP has a crucial role in the long‐term maintenance of neurogenic vasodilation on the periphery ().…”