Phenylephrine-induced antinociception: investigations of potential neural and endocrine bases

Acute hypertensive states can produce antinociception, largely via unknown mechanisms. The aim of the present series of experiments was to examine potential hormonal and neural bases of analgesia induced by i.v. infusion of the pressor (hypertensive) agent phenylephrine. All rats were implanted with right jugular and left carotid cannulae for phenylephrine infusion and blood pressure/heart rate monitoring, respectively, and were tested approximately 24 h later in the unanesthetized state. The tail-flick test was used to measure responsivity prior to, during, and after phenylephrine infusion. Potential adrenal and pituitary contributions to phenylephrine-induced antinociception were examined, respectively, by physical disruption of adrenal blood flow and pharmacological suppression of pituitary activation. Acute block of all adrenal hormones, via closure at the time of testing of pre-implanted adrenal ligatures, did not block phenylephrine antinociception. However, pharmacological suppression of pituitary activation via pretreatment with the synthetic glucocorticoid dexamethasone abolished phenylephrine antinociception. Intriguingly, dexamethasone had no noticeable effect on urination prior to phenylephrine administration, yet only dexamethasone-treated rats exhibited copious urination during phenylephrine infusion. This suggests that the hypertensive agent phenylephrine releases vasopressin from the posterior pituitary terminals of the paraventricular hypothalamus (PVH) in a dexamethasone-suppressible manner, possibly via the known baroreceptor-nucleus tractus solitarius (NTS)-PVH link. Since (1) bilateral lesions of the spinal cord dorsolateral funiculus (DLF) were shown in the current study to abolish phenylephrine antinociception, (2) PVH is known to send vasopressinergic projections to the spinal cord via the DLF, and (3) intrathecal vasopressin produces antinociception via V1-like vasopressin receptors, the effect of an intrathecal V1 vasopressin antagonist was tested on phenylephrine-induced antinociception. The V1 vasopressin antagonist blocked phenylephrine antinociception, suggesting that phenylephrine antinociception may be mediated by a baroreceptor-NTS-PVH-DLF circuit leading to vasopressin release at spinal levels.