δ‐Opioid agonist, [D‐Pen2,5]enkephalin (DPDPE) attenuates the exercise pressor reflex in both freely perfused and ligated rats

A reflex, which is elicited by mechanical and metabolic stimuli arising in contracting muscles, is responsible in part for the increases in cardiac output, heart rate, and arterial pressure evoked by exercise. In patients with peripheral artery disease, this reflex is exaggerated and may contribute to their increased risk of adverse cardiovascular events. The afferent arm of this reflex, which is called the exercise pressor reflex (EPR), is comprised of group III and IV afferents. Both μ and δ opioid receptors are expressed on the spinal endings of these afferents which terminate in the dorsal horn of the spinal cord. Evidence suggests that δ‐opioid receptors (DOR) are expressed predominately on the spinal endings of thinly myelinated Aδ fibers (group III), whereas μ‐opioid receptors (MOR) are expressed predominately on the spinal endings of C‐fibers (group IV). Using stimuli that activated group III afferents, namely static contraction, tendon stretch, and lactic acid, we tested the hypothesis that activation of pre and postsynaptic DOR in the dorsal horn attenuated the pressor reflexes in both rats with freely perfused hindlimb muscles and in rats with hindlimb muscles whose arterial supply had been ligated for 72 hours. We activated DOR by intrathecal injection (10μg in 10μl) of the selective δ‐opioid agonist, [DPen2,5] enkephalin (DPDPE). We found that in freely perfused rats, DPDPE significantly attenuated the EPR evoked by static contraction ( n=7; P <0.005) and the muscle mechanoreflex, the latter of which was evoked by stretching the calcaneal tendon (n=9; P <0.05). Likewise, DPDPE attenuated the pressor response to injection of lactic acid into the arterial supply of the hindlimb (n=7; P <0.05). in contrast, DPDPE did no attenuate the pressor response to arterial injection of capsaicin (n=7; P>0.5), which is a more selective stimulus to group IV afferents than it is to group III afferents. In ligated rats, DPDPE attenuated the EPR, the muscle mechanoreflex (both n=6; P<0.05) as well as the pressor response to arterial injection of lactic acid (n=6; P< 0.05). In ligated rats, however, DPDPE did not attenuate the pressor response to capsaicin (n=8; P>0.05). Intrathecal injection of saline (10μl), the vehicle for DPDPE, did not affect the EPR, the muscle mechanoreflex or the pressor responses to lactic acid or capsaicin in either FP or ligated rats. We conclude that activation of δ‐opioid receptors in the dorsal horn attenuates reflexes evoked by group III muscle afferents in both freely perfused and ligated rats. Support or Funding Information This work was funded by National Institutes of Health grants R01 AR059397 and P01 HL134609. The NIH is thanked for their support of this work. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .