Chronic constriction injury (CCI) of the rat sciatic nerve, produces an animal
model ofperipheral neuropathy exhibiting abnormal pain states similar to those seen
in man, including behavioural signs of spontaneous pain, hyperalgesia and allodynia.
Many components ofneuropathic pain are resistant to classical opioid analgesics, and
anaesthetic nerve blocks or surgical sympathectomies often provide only temporary
relief. Since the expression ofVasoactive Intestinal Polypeptide (VIP) and Pituitary
Adenylate Cyclase-Activating Polypeptide (PACAP) is markedly up-regulated in
dorsal root ganglia following peripheral nerve injury, we investigated whether
VIP/PACAP receptors are important regulators of the amplified sensory responses
which develop following neuropathy.
This study addressed the role of VIP₁, VIP₂ and PACAP receptors with regard
to the responses of dorsal horn neurones in normal compared to CCI animals, using
novel selective agonists and antagonists. In electrophysiological experiments on
anaesthetised rats, the effects of ionophoretic application of VIP₁, VIP₂ and PACAP
receptor antagonists were investigated on neuronal activity induced by innocuous
brushing or cold stimulation of the cutaneous receptive field, or following peripheral
application of the chemical algogen mustard oil. In normal rats, VIP₁ and PACAP
receptor antagonists appeared to exert a general modification of dorsal horn neurone
responses, inhibiting both brush- and mustard oil-induced activity to similar extents.
In contrast, a novel VIP₂ receptor antagonist selectively inhibited mustard oil-evoked
activity, whilst showing negligible effects on brush-evoked activity.
The effects of the VIP/PACAP receptor antagonists changed markedly in CCI
animals so that antagonists for all three receptor subtypes showed negligible effects
on brush-induced activity of dorsal horn neurones. In contrast, VIP,/PACAP
receptor antagonists significantly inhibited cold-induced activity, while a VIP₂
receptor antagonist had little effect. However, mustard oil-induced activity was
significantly inhibited by all three receptor antagonists in CCI animals.
The activity of single, multireceptive dorsal horn neurones was markedly
increased following ionophoretic administration of selective VIP₁, VIP₂ and PACAP
receptor agonists both in normal and CCI rats. Following nerve injury however, two
main differences were apparent, and these may reflect changes in receptor
expression: the number of dorsal horn neurones activated by the VIP2 receptor
agonist doubled (these neurones also showed a greater extent of cell activation than
those excited in normal animals), while the percentage of neurones activated by the
VIP, receptor agonist was seen to decrease. The proportion of cells activated by the
PACAP receptor agonist remained unchanged.
In addition, in situ hybridisation histochemistry (ISHH) detection ofmRNA
for the three receptor subtypes, was employed to monitor any changes in receptor
expression following nerve injury. This study revealed that CCI of the rat sciatic
nerve produced a significant increase in the expression of VIP₂ receptor mRNA in
laminae III/IV of the spinal dorsal horn. In contrast, VIP₁ receptor mRNA was seen
to markedly decrease, while the expression of mRNA for the PACAP receptor
appeared to be unchanged.
In conclusion, these results provide evidence that VIP/PACAP receptors may
be important mediators/modulators ofthe transmission of sensory information at the
spinal cord level, underlining the potential for VIP/PACAP receptor antagonists as
new analgesics, particularly for use in currently intractable neuropathic pain states.
These data demonstrate the involvement of the VIP₂ receptor in the transmission of
nociceptive (C-fibre-mediated) information, both in normal and neuropathic animals.
Although VIP, and PACAP receptor antagonists are rather non-selective inhibitors of
sensory inputs in normal states, they may represent useful analgesics for certain
aspects of allodynia (for example cold) as well as for polymodal C-fibre responses in