Tonic Pain Perception in the Mouse: Differential Modulation by Three Receptor-selective Opioid Agonists

The proposition that tonic nociception models are more analogous to clinical pain than traditional acute models prompted our previous development of a modified mouse paw formalin test. To discern possible modulatory roles and site(s) of action of endogenous opioid systems, the receptor-preferring agonists sufentanil (mu), U-50,488H (kappa) and [D-Pen2,5]enkephalin (DPDPE, delta) were evaluated for antinociceptive activity in the formalin paradigm by systemic (except DPDPE), spinal and supraspinal routes. All observations were done under blind conditions. Doses causing overt behaviors that indicated a breach of receptor specificity (during the observation period) were rejected. Higher doses of centrally administered DPDPE (greater than 0.3 micrograms/mouse, intrathecal; greater than 3 micrograms/mouse, intracerebroventricular) induced a behavioral syndrome traditionally associated with mu agonism, and thus were not considered for this study. A50 values from behaviorally acceptable dose ranges for mean percent analgesia (reduction of paw licking compared to controls) were: trans-(+/- )-3,4-dichloro-N-methyl-N-[U-50,488H 2-pyrrolidinyl)cyclohexyl]-benzeneacetamide methanesulfonate,U-50,488H--3200 nmol/kg, subcutaneous, 1100 nmol/kg, intrathecal and 314 nmol/kg, intracerebroventricular; sufentanil--11.1 nmol/kg, subcutaneous, 8.6 nmol/kg, intrathecal; and DPDPE--inactive. On the basis of our dose-response data, we suggest that, in mice, kappa and mu, but not delta, opioid receptors modulate tonic pain perception at both spinal and supraspinal loci. The results also support inclusion of the modified formalin test in preclinical evaluations of potential kappa agonists.