Vol. 284, Issue 1, 378-387, 1998

Differential Effects of Intrathecally Administered Delta and Mu Opioid Receptor Agonists on Formalin-Evoked Nociception and on the Expression of Fos-like Immunoreactivity in the Spinal Cord of the Rat¹

Donna L. Hammond, Huilan Wang, Nora Nakashima and Allan I. Basbaum

Department of Anesthesia and Critical Care, University of Chicago, Chicago, Illinois (D.L.H.) and Departments of Anatomy and Physiology, W.M. Keck Center for Integrative Sciences, University of California at San Francisco, San Francisco, California (H.W., N.N. and A.I.B.)

This study examined the effects of intrathecally (i.t.) administered mu and delta opioid receptor agonists on the flinching behavior and the expression of Fos-like immunoreactivity (Fos-LI) in the spinal cord elicited by s.c. injection of 5% formalin in one hindpaw of the rat. Intrathecal pretreatment with either the delta-1 opioid receptor agonist [D-Pen^2,5]enkephalin (DPDPE) or the delta-2 opioid receptor agonist [D-Ala²,Glu⁴]deltorphin (DELT) produced a dose-dependent inhibition of flinching behavior in phase 1 and phase 2 that was antagonized by coadministration of the delta-1 opioid receptor antagonist 7-benzylidinenaltrexone or the delta-2 opioid receptor antagonist Naltriben, respectively. Although i.t. pretreatment with 60 µg of DPDPE produced a small decrease in the numbers of Fos-LI neurons in laminae I, IIi and IIo, as well as laminae V and VI and laminae VII-X, i.t. pretreatment with 30 µg of DELT did not decrease the number of Fos-LI neurons in any region of the spinal cord. In contrast, i.t. pretreatment with an equieffective dose of the mu opioid receptor agonist [D-Ala²,NMePhe⁴,Gly-ol⁵]enkephalin (DAMGO) not only significantly decreased the number of flinches in phase 1 and phase 2, but also nearly completely prevented the expression of Fos-LI in all regions of the spinal cord. These effects were antagonized by pretreatment with the mu opioid receptor antagonist D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Phe-Thr-NH₂. The efficacy of i.t. administered DAMGO suggests that a direct spinal action contributes to the inhibition of noxious stimulus-evoked Fos-LI in the spinal cord produced by systemically administered mu opioid receptor agonists such as morphine. The relative lack of effect of DPDPE or DELT suggests that delta opioid receptors do not modulate the early-immediate gene c-fos. Alternatively, because delta opioid receptor agonists inhibit synaptic transmission in the spinal cord by predominantly presynaptic mechanisms and do not hyperpolarize dorsal horn neurons, the excitatory inputs that persist in the presence of these agonists may be sufficient to activate the c-fos gene. Taken together, these results provide new evidence, at the level of a "third messenger," that the antinociception produced by i.t. administration of delta and mu opioid receptor agonists is mediated by different mechanisms.