A substance P-opioid chimeric peptide as a unique nontolerance-forming analgesic

To elucidate mechanisms of acute and chronic pain, it is important to under stand how spinal excitatory systems influence opioid analgesia. The tachyki nin substance P (SP) represents the prototypic spinal excitatory peptide ne urotransmitter/neuromodulator, acting in concert with endogenous opioid sys tems to regulate analgesic responses to nociceptive stimuli. We have synthe sized and pharmacologically characterized a chimeric peptide containing ove rlapping NH2- and COOH-terminal functional domains of the endogenous opioid endomorphin-2 (EM-2) and the tachykinin SP, respectively. Repeated adminis tration of the chimeric molecule YPFFGLM-NH2, designated ESP7, into the rat spinal cord produces opioid-dependent analgesia without loss of potency ov er 5 days. In contrast, repeated administration of ESP7 with concurrent SP receptor (SPR) blockade results in a progressive loss of analgesic potency, consistent with the development of tolerance. Furthermore, tolerant animal s completely regain opioid sensitivity after post hoc administration of ESP 7 alone, suggesting that coactivation of SPRs is essential to maintaining o pioid responsiveness. Radioligand binding and signaling assays, using recom binant receptors, confirm that ESP7 can coactivate mu-opioid receptors (MOR ) and SPRs in vitro. We hypothesize that coincidental activation of the MOR - and SPR-expressing systems in the spinal cord mimics an ongoing state of reciprocal excitation and inhibition, which is normally encountered in noci ceptive processing. Due to the ability of ESP7 to interact with both MOR an d SPRs, it represents a unique prototypic, anti-tolerance-forming analgesic with future therapeutic potential.