Nocistatin and Prepro-Nociceptin/Orphanin FQ 160–187 Cause Nociception through Activation of G_i/oin Capsaicin-Sensitive and of G_sin Capsaicin-Insensitive Nociceptors, Respectively

Abstract

Nociceptin/orphanin FQ (N/OFQ), nocistatin, and prepro-N/OFQ 160 -187 (C-peptide) are all derived from the same precursor protein. We examine the pharmacological mechanisms of nocistatin-and C-peptide-induced pronociceptive responses in a novel algogenic-induced nociceptive flexion test in mice. The intraplantar (i.pl.) injection of nocistatin-and C-peptide induced pronociceptive responses in a range of 0.01 to 10 or 1 pmol, respectively, which showed 100-to 1000-fold less potent effects than the N/OFQ. The nociceptive effects of both peptides were not affected by 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazole-2-one (J-113397) (i.pl.), an N/OFQ receptor antagonist, indicating that they are mediated by a novel mechanism independent of activation of N/OFQ receptor. Like N/OFQ, nocistatin-induced nociception was abolished by i.pl. injection of pertussis toxin, phospholipase C inhibitor, or CP-99994, a neurokinin 1 receptor antagonist, indicating that nocistatin may elicit nociception through a substance P release from nociceptor endings via activation of G i/o and phospholipase C. The nociception was abolished by neonatal pretreatment (s.c.) with capsaicin or by i.t. pretreatment with CP-99994, but not , an N-methyl-D-aspartate receptor antagonist. In contrast, C-peptide-induced nociception was attenuated by the pretreatment with antisense oligodeoxynucleotide for G␣ s (i.t.) and with KT-5720 (i.pl.), a cyclic AMP-dependent protein kinase inhibitor, but not with pertussis toxin. The nociception was neither attenuated by neonatal capsaicin nor by i.t. injection with CP-99994, but it was attenuated by i.t. injection with MK-801. These results suggest that nocistatin and C-peptide derived from prepro-N/OFQ stimulate distinct nociceptive fibers through different in vivo signaling mechanisms.Nociceptin/orphanin FQ (N/OFQ), discovered as the endogenous peptide ligand for N/OFQ receptor/NOP (Meunier et al., 1995;Reinscheid et al., 1995), is generated from a larger precursor protein, prepro-N/OFQ (Saito et al., 1995;Mollereau et al., 1996;Nothacker et al., 1996). N/OFQ has been seen as active at multiple sites of nociceptive transmission, ranging from peripheral nociceptors (Inoue et al., 1998) to nociceptive centers in the brain (Morgan et al., 1997). Pharmacologically, the actions of N/OFQ are complex and seem to be contradictory; intracerebroventricular or intrathecal (i.t.) administration of this peptide exerts pronociceptive (or hyperalgesia) and/or analgesia (for reviews, see Calo, 2000;Mogil and Pasternak, 2001). We also previously reported that N/OFQ (i.t.) exerts nocifensive actions in a femtomolar dose range through a substance P release from primary substance P fibers, whereas analgesic actions in a nanomolar dose range come through an inhibition of substance P actions on the second-order neuron in the spinal cord (Inoue et al., 1999). These findings suggest that the opposing actions of N/OFQ may depend on the dose administered.However, nocistatin, another...

Identification of NIPSNAP1 as a Nocistatin-interacting Protein Involving Pain Transmission

“…NST inhibits N/OFQ-induced pain transmission such as allodynia and hyperalgesia (12)(13)(14), inflammatory pain responses (15)(16)(17), and morphine tolerance (18,19). The mature form of NIPSNAP1 was expressed in various regions of the brain and spinal cord (Fig.…”

“…NST itself exerts inhibitory effects, such as inflammatory pain responses (11)(12)(13) and morphine tolerance (14,15). NST also induces pronociceptive effects in inflammatory pain response at high doses (nmol) (16,17) and nociceptive flexor reflexes (18). In addition to pain transmission, NST is involved in other central nervous functions such as learning and memory (19), feeding (20), and anxiety (21,22).…”

Pharmacological and Molecular Characterization of the Mechanisms Involved in Prostaglandin E2-Induced Mouse Paw Edema

“…The doses of all inhibitors used in this study were chosen on the basis of literature data or preliminary experiments (Santos and Calixto, 1997;Beirith et al, 2003;Inoue et al, 2003;da Cunha et al, 2004;Ferreira et al, 2004Ferreira et al, , 2005.…”

Nocistatin sensitizes TRPA1 channels in peripheral sensory neurons

“…[17][18][19] The pro-nociceptive action of Nocistatin in these pain paradigms has so far been attributed to attenuation of inhibitory neurotransmission in the spinal cord 12 and/or facilitation of neurotransmitter release from a population of capsaicin-sensitive (and therefore TRPV1-expressing) peripheral sensory neurons. 25 It is noteworthy that a large subset of capsaicin-sensitive TRPV1-positive sensory neurons also expresses TRPA1 channels. 10,20 However, despite the apparent co-expression of both channels, cellular responses to TRPV1 activation were unaffected by Nocistatin in our experiments arguing for a certain degree of specificity of the observed TRPA1 sensitization by Nocistatin.…”