Changes induced by formalin pain in central α₁-adrenoceptor density are modulated by adenosine receptor agonists

We aimed to elucidate the role of α₁-adrenoceptors in adenosine analgesia in the formalin test. Formalin was injected into the hind paw of male CD-1 mice after injection of adenosine A₁ or A_2a receptor agonists, CPA, [N(6)-cyclopentyladenosine], and CGS21680 [2-p-(2-carboxyethyl)-phenylethylamino-5′-N-ethylcarboxamidoadenosine hydrochloride]. In the behavioral experiment, α₁-adrenoceptors were blocked by an α₁-adrenoceptor antagonist prazosin, 0.01 mg/kg i.p., and the time mice spent paw licking was recorded for the early (0–15 min) and late (15–60 min) phase of formalin pain. In the neurochemical experiments, mice were killed 15 or 45 min after formalin injection. The density of α₁-adrenoceptors was assessed in various brain areas and in the lumbar spinal cord by [³H]prazosin autoradiography. Adenosine agonists produced analgesia in both phases of formalin pain, while prazosin showed a tendency to pronociceptive action in the late phase, and antagonized the effect of CGS21680. After formalin injection, α₁-adrenoceptor density was elevated in some brain areas, mainly in the late phase (some contralateral amygdaloid and ipsilateral thalamic nuclei) and depressed in others (early phase in the ipsilateral spinal cord and late phase in both ipsi- and contralateral sensorimotor cortex). Elevation of α₁-adrenoceptor density, which may be interpreted as a defensive response, did not develop in several cases of CPA-pretreated mice. This suggests that the analgesic effect of adenosine A₁ receptor activation renders the defensive response unnecessary. The depression of α₁-adrenoceptors may suggest development of hypersensitivity in a given structure, and this was antagonized by CGS21680, suggesting the role of A_2a receptors in control of inflammatory formalin pain.