The role of VIP/PACAP receptor subtypes in spinal somatosensory processing in rats with an experimental peripheral mononeuropathy

Abstract

Peripheral nerve damage often results in the development of chronic pain states, resistant to classical analgesics. Since vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are up-regulated in dorsal root ganglion cells following peripheral nerve injury, we investigated the expression and influence of VPAC1, VPAC2 and PAC1 receptors in rat spinal dorsal horn following a chronic constriction injury (CCI). Electrophysiological studies revealed that selective antagonists of VPAC1, VPAC2 and PAC1 receptors inhibit mustard oil-, but not brush-induced activity of dorsal horn neurones in CCI animals, while cold-induced neuronal activity was attenuated by VPAC1 and PAC1, but not VPAC2 receptor antagonists. Ionophoresis of selective agonists for the receptor subtypes revealed that the VPAC2 receptor agonist excited twice as many cells in CCI compared to normal animals, while the number of cells excited by the VPAC1 receptor agonist decreased and responses to PACAP-38 remained unchanged. In situ hybridisation histochemistry (ISHH) confirmed an increase in the expression of VPAC2 receptor mRNA within the ipsilateral dorsal horn following neuropathy, while VPAC1 receptor mRNA was seen to decrease and that for PAC1 receptors remained unchanged. These data indicate that VIP/PACAP receptors may be important regulatory factors in neuropathic pain states.

Expression of Phosphorylated cAMP Response Element Binding Protein (p-CREB) in Bladder Afferent Pathways in VIP−/− Mice with Cyclophosphamide (CYP)-Induced Cystitis

“…Thus, absence of VIP in the VIP −/− mice could produce a direct effect on primary afferent cells. However, VIP acting through VIP receptors activates adenylate cyclase (Ishihara et al, 1992), increasing cAMP and inducing phosphorylation of CREB by cAMP dependent protein kinase A (Delgado et al, 1999;Dickinson et al, 1999;Delgado et al, 2000;Mayr and Montminy, 2001). Thus, in VIP −/− mice, one might have expected a decrease in pCREB expression in DRG cells if VIP at the level of the DRG directly mediated changes in pCREB expression.…”

“…In this study, we have examined the contribution of vasoactive intestinal polypeptide (VIP) in afferent pathways to the urinary bladder by using wildtype and VIP −/− mice under control conditions or after induction of acute bladder inflammation. VIP is a 28 amino-acid peptide, belonging to the glucagon/secretin superfamily of hormones (Dickinson et al, 1999) and acts through two high affinity receptors, the VPAC 1 and VPAC 2 receptors (Harmar et al, 1998). VIP may exert excitatory or inhibitory actions in neural pathways controlling micturition and these functions may be altered with neural injury, disease or inflammation.…”

Involvement of PACAP receptor in primary afferent fibre‐evoked responses of ventral roots in the neonatal rat spinal cord

“…As mentioned in the introduction, VPAC 1 receptor mRNA is most widely expressed and VPAC 2 and PACAP receptor mRNAs are sparsely expressed in the adult rat spinal cord (Dickinson et al, 1999). On the other hand, the data indicate that, in the neonatal rat spinal cord, VPAC 1 receptor mRNA is not expressed and PACAP receptor is the most abundant receptor among the receptors for PACAP.…”

“…However, it is supposed that PACAP receptor is dominantly expressed, and that there may be only a small number of VPAC 2 receptors It has been reported that PACAP(6-38) inhibited sustained neuronal ®ring of the wide dynamic range (WDR) neurons of adult rat spinal cord induced by topical application of mustard oil to the skin (Dickinson et al, 1997). PACAP(6-38) also demonstrates inhibition of sustained neuronal ®ring of the WDR neurons induced by 58C cold stimulation in the rats with an experimental peripheral mononeuropathy (Dickinson et al, 1999). As mentioned above, PACAP(6-38) interacts with both PACAP receptor and VPAC 2 receptor (Dickinson et al, 1997) and the data of the study using PACAP(6-38) did not reveal which receptor, PACAP or VPAC 2 , is important for the transmission of nociceptive information in the spinal cord.…”

“…The PACAP receptor displays a much greater anity for PACAP38 and PACAP27 than VIP, and the VPAC 1 and VPAC 2 receptors display no marked selectivity for any of them (Ishihara et al, 1992;Spengler et al, 1993). VPAC 1 receptor mRNA appeared to be most widely expressed within the adult rat spinal cord, occurring in a moderate number of lamina II cells and also in laminae III ± IV, and VPAC 2 and PACAP receptor mRNAs were sparsely expressed through laminae II ± IV of the dorsal horn (Dickinson et al, 1999). Distinct distribution of these receptors in the spinal cord suggested that they may have distinct functional roles in the spinal cord.…”