Norepinephrine-induced nociception and vasoconstrictor hypersensitivity in rats with chronic post-ischemia pain

Painful hypersensitivity to norepinephrine (NE) has been reported in various chronic pain conditions that exhibit sympathetically-maintained pain (SMP), particularly CRPS-I and II. We investigated the parallels between the nociceptive and vascular sensitivity to NE in rats with chronic post-ischemia pain (CPIP), an animal model of CRPS-I induced by hind paw ischemia-reperfusion injury. Intradermal injections of NE to the affected hind paw induced dose-dependent nociceptive behaviours in CPIP rats, but not sham animals. These behaviours were blocked by alpha(1)- and alpha(2)-adrenergic receptor antagonists, or a nitric oxide (NO) donor. Using laser Doppler flowmetry, we detected vasoconstrictor hypersensitivity in the ipsilateral CPIP hind paw, as compared to responses in sham animals or the contralateral hind paw. The vasoconstrictor hypersensitivity was also attenuated by adrenergic antagonists. Intradermal injection of [Arg(8)] vasopressin (AVP) or the endothelial NO synthase (eNOS) inhibitor, L-NIO, to the affected paw also induced nociceptive behaviours in CPIP rats, but not sham rats. These results suggest CPIP rats display abnormal nociceptive responses to adrenergic and non-adrenergic vasoconstrictive agents. Furthermore, the nociceptive responses to NE in CPIP rats are paralleled by enhanced vasoconstrictive responses to NE, and are relieved by alpha-adrenergic antagonists or a vasodilator. We conclude that persistent tissue ischemia and hypersensitivity to sympathetic vasoconstriction are important mechanisms for pain in CPIP rats, and that either reducing vasoconstriction or enhancing vasodilatation may be effective methods of relieving the pain of CRPS-I.