Analgesic and tolerance-inducing effects of the highly selective δ opioid agonist enkephalin in mice

The novel and highly selective, conformationally restricted enkephalin analogue for δ-opioid receptors, enkephalin (DPDPE; Pen = penicillamine), was studied in various in vivo tests for analgesia, tolerance and physical dependence. Intracerebroventricular (i.c.v.) administration of DPDPE caused a dose-dependent, naloxone-reversible antinociception, measured with the heat-irradiant (tail-flick) method. Acute tolerance developed to the antinociceptive effect of DPDPE. DPDPE also caused mild signs of physical dependence (withdrawal hypothermia and body weight loss) after repeated peptide treatment. Severe signs of morphine withdrawal (e.g. withdrawal jumping) on the other hand, could not be reversed by the administration of DPDPE. It is concluded that the activation of central δ-opioid receptors may play a role in controlling pain mechanisms, and that this activation is followed by the rapid development of a tolerance to this action.