Opioid Receptors

Opioid receptors are glycoproteins found in cell membranes at multiple sites in the central nervous system and in the periphery. Opioid receptors have multiple subtypes; the most important are |i, k, and 8, and the opioid receptor-like receptor (ORL) (Table 7.1). Morphine and morphine-like opioids bind primarily to the | receptors. These receptors are located in the periaqueductal gray matter (brain) and the substantia gelatinosa (spinal cord) (Carr and Lipkowski 1993). |i receptors can be further subdivided into |1 and |2 receptors. |1 activation produces analgesia, and |2 activation produces euphoria, respiratory depression, nausea, vomiting, decreased gastrointestinal motility, urinary retention, tolerance, dependence, histamine release, miosis, and/or anorexia (Ferrante 1993). The structural andpharmacochemical differences between opioid agonists can affect the binding and affinity with the mu receptor leading to varied analgesic responses.

At present, pharmaceutical researchers are trying to develop a |1 opioid-specific agonist to eliminate the many unwanted side effects caused by activation of |2 receptors. These mu receptor subtypes can lead to a patient responding better to one opioid versus another for adequate pain control and also to the phenomenon of cross-tolerance. Cross-tolerance is related to different subtypes of receptors, such as the activity of kappa and delta opioids mediating analgesia in the presence of high doses of mu opioid agonists. k receptor activation causes analgesia (visceral and spinal), sedation, dysphoria, hallucinations, and less respiratory depression compared to |i receptors (Mogil and Pasternal 2001). Peripheral k

Table 7.1 Four major subtypes of opioid receptors.





Delta (8)

81' 82

• Brain o Pontine nuclei o Amygdala o Olfactory bulbs o Deep cortex

• Antidepressant effects

• Physical dependence

Kappa (k)

k1> k2' k3

• Brain o Hypothalamus o Periaqueductal gray o Claustrum

• Spinal cord o Substantia gelatinosa

• Spinal analgesia

• Inhibition of ADH release



• Brain o Cortex (laminae III and IV) o Thalamus o Striosomes o Periaqueductal gray

• Spinal cord o Substantia gelatinosa

• Intestinal tract

• Supraspinal analgesia

• Physical dependence

• Respiratory depression

• Reduced GI motility

• Physical dependence

• ?



• Brain



o Cortex o Amygdala o Hippocampus o Septal nuclei o Habenula • Hypothalamus

• Depression

• Development of tolerance to |i agonists

Modified from Janet C. Hsieh and Daniel B. Carr, Massachusetts General Hospital Handbook of Pain Management, Lippincott Williams and Wilkins, 2005.

Modified from Janet C. Hsieh and Daniel B. Carr, Massachusetts General Hospital Handbook of Pain Management, Lippincott Williams and Wilkins, 2005.

receptors have been found in the gastrointestinal tract, muscle, skin, connective tissues, and kidneys, where their activation can result in oliguria and antidiuresis. The primary endogenous ligand for k receptors is dynorphin A. The 8 receptor facilitates |x receptor activity and enhances supraspinal and spinal analgesia. The primary endogenous ligand for 8 receptors is enkephalin. The ORL receptor is similar in structure to the classical opioid receptors (|i, k, and 8), but the classical ligands do not have a high affinity for it. A new neuropeptide, termed orphanin FQ (nociceptin), was found to have a high affinity for the ORL-1 receptor (Borsook 1994). Orphanin FQ has potent anti-analgesic actions supraspinally and analgesic actions spinally. Other orphanin FQ activities are less clear. The diversity of responses might reflect ORL-1 receptor heterogeneity, but more studies are needed on this novel substance. The N-methyl-D-aspartate (NMDA) receptor is associated with opioid tolerance and is involved with nociceptive transmission in the spinal dorsal horn (Borsook 1994), as shown for the | receptor in Fig. 7.1. The NMDA receptor is an inotropic receptor for glutamate and is distinct in that it is both ligand-gated and voltage-dependent. Methadone, dextromethorphan, ketamine, and tramadol are all examples of NMDA receptor antagonists. NMDA receptor antagonists can reduce the incidence of tolerance to morphine or other opiate agents.

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