Endomorphins: Novel Endogenous μ‐Opiate Receptor Agonists in Regions of High μ‐Opiate Receptor Density

Abstract

Endomorphin-1 (Tyr-Pro-Trp-Phe-NH2, EM-1) and endomorphin-2 (Tyr-Pro-Phe-Phe-NH2, EM-2) are peptides recently isolated from brain that show the highest affinity and selectivity for the mu (morphine) opiate receptor of all the known endogenous opioids. The endomorphins have potent analgesic and gastrointestinal effects. At the cellular level, they activate G-proteins (35S-GTP gamma-S binding) and inhibit calcium currents. Support for their role as endogenous ligands for the mu-opiate receptor includes their localization by radioimmunoassay and immunocytochemistry in central nervous system regions of high mu receptor density. Intense EM-2 immunoreactivity is present in the terminal regions of primary afferent neurons in the dorsal horn of the spinal cord and in the medulla near high densities of mu receptors. Chemical (capsaicin) and surgical (rhizotomy) disruption of nociceptive primary afferent neurons depletes the immunoreactivity, implicating the primary afferents as the source of EM-2. Thus, EM-2 is well-positioned to serve as an endogenous modulator of pain in its earliest stages of perception. In contrast to EM-2, which is more prevalent in the spinal cord and lower brainstem, EM-1 is more widely and densely distributed throughout the brain than EM-2. The distribution is consistent with a role for the peptides in the modulation of diverse functions, including autonomic, neuroendocrine, and reward functions as well as modulation of responses to pain and stress.

Applications of Gene Therapy to the Treatment of Chronic Pain

“…In the past decade the endomorphins EM-1 (Tyr-Pro-Trp-Phe-NH2) and EM-2 (TyrPro-Phe-Phe-NH2) were identified from bovine brain extracts as highly selective mu receptor agonists and appear to represent the endogenous ligands of the mu receptor [23]. While EM-1-like immunoreactivity is primarily restricted to brain, EM-2-like immunoreactivity is found primarily in the spinal cord and peripheral nervous system and may modulate spinal level pain signaling [24]. Despite the isolation of EM peptides from tissue however, the identity of the gene(s) encoding the precursor protein(s) from which the endomorphin peptides are derived has not been reported, which posed a challenge to gene transfer.…”

Antidepressant-Like Effect of Endomorphin-1 and Endomorphin-2 in Mice

“…Radioimmunological and immunocytochemical analyses revealed that both endomorphins are densely distributed throughout the central nervous system, near neurons expressing the m-opioid receptors Zadina et al, 1999;Zadina, 2002). Endomorphins were found in the limbic system (septum, nucleus accumbens, amygdala), thalamic nuclei, locus coeruleus, and in the brain stem (Schreff et al, 1998;Martin-Schild et al, 1999;Zadina, 2002).…”

Chronic arthritis down‐regulates peripheral μ‐opioid receptor expression with concomitant loss of endomorphin 1 antinociception

“…Recently, an endogenous tetrapeptide called endomorphin was isolated from bovine and human brain; endomorphin has at least equal affinity but greater specificity for the -opioid receptor than any other known synthetic or natural ligand (14,15). Two forms of endomorphin have been identified, of which endomorphin 1 is the most widely distributed and potent in controlling pain (16). The analgesic capacity of endomorphin 1 is generally equipotent with that of morphine but in some models is more effective than morphine and other -opioid receptor agonists (for review, see ref.…”