Providing straightforward information pertaining to drugs, drug use & drug policy. The Grey Pages promotes drug-related literacy and advocates a system of viable and tolerant drug policies. This is my personal collection of commentaries, essays, tid-bits, and other such writings on everything ranging from drug use, drug policy and drug-myths, to drug-science, addiction, human behavior, and the workings of the human brain. I started this blog with a particular focus on opioids, and over the past year have found my interest gravitate toward the intriguing, ever-changing world of designer intoxicants (i.e. "research chemicals" or "designer drugs").

Friday, March 30, 2012

How Do Opioid Analgesics Work? (Re-Run)

This piece deals primarily with the pharmacological mechanisms of opioids in relieving pain and promoting a sense of well being.

Opioid Analgesic Pharmacology:

Opioid drugs produce their analgesic and euphoric effects by binding to opioid receptors located throughout the brain and spinal cord. There are three primary subtypes of receptor - mu (micro or 'morphine' receptor), delta, and kappa) Most effects of clinical value are mediated via the mu receptor subtype, producing anlgesia and a sense of well being.

Opioid agonists bind to various receptor types each with a varying degree of selectivity and affinity, but the more common opioid analgesics interact predominantly with the micro receptor. The binding affinities and intrinsic activities of each opioid are unique and account for a wide variation of potency and efficacy across the opioid family. Differences in the pharmacological & clinical properties among opioids may be subtle or stark, yet all mu-opioid agonists produce a similar spectrum of analgesic and in some cases euphoric effects. Mu-agonist analgesics all share a degree of cross tolerance & clinical interchangeability.

The subjective effects of opioids are reflective not only of their pharmacological properties, but of the distribution of the drug throughout various CNS and peripheral tissues in addition to the densities of various receptors throughout these different anatomical locations. The effects are also dependent to a large degree on individual interpretation, behavioral, contextual and environmental factors. Many individuals who use opioids for pain relief experience little euphoria; while many individuals who use opioids for pleasure experience little pain relief.

Aside from anatomical distribution of the opioid receptors, there are two primary pharmacological determinants of an opioid....

Source: zuniv.net (right click for larger view)
Binding Affinity - is the degree of strength at which the compound binds to a given receptor type/subtype. More simply, the level of 'attraction' between a compound and a given receptor. Example, morphine while having a high affinity for the mu receptor, has little affinity for kappa receptors. Fentanyl shows very high affinity for mu receptors, but no affinity for delta or kappa receptors.

Intrinsic Activity - is the way in which a compound behaves once bound to a given receptor. An opioid agonist binds to receptors and triggers a positive neurological response, producing a positive effect; an opioid antagonist binds to receptors, but activates no response or effect and may simply block the effects of other opiates. Some opioids act as partial agonists and produce a limited intrinsic response. Furthermore, one must consider the potency of the compound's activity or signal at a particular receptor; i.e. a weak binding affinity does not indicate a weak signal.

Ascending Pain Pathways:

All three major types of opioid receptors play some role in analgesia at the spinal level. Mu, delta, and kappa sites are distributed, pre and post synaptically, within the grey matter of the spinal cord, most densely in the outermost layers (lamina I and II), and less so in the deeper layers. In the dorsal horn (section of grey matter nearest to the surface of the back), mu receptors account for around 70% of receptors, delta for 24%, and kappa for 6%.

 delta A and C fibers relay signals to 2nd
order neurons of the spinothalamic tract
This takes place at two different locations
in the grey matter of the spinal cord
Activation of opioid receptors on the surface of ascending delta A and C fibers in the substantia galatinosa inhibit the transmission of pain transmitters between the ascending A and C fibers and the spinothalamic tract, which carries pain signals to the brain. Opioid activity inhibits the firing of multiple pain-mediating transmitters, including glutamate, nociceptin, and substance P.

C fibers carry sensations of dull, poorly localize, slower conducting pain; while A delta fibers carry sharp and rapid conducting pain.

While C fibers synapse to the spinothalamic tract in the SG layers,  most A fibers terminate in a different area, specifically, the nucleus proprius. So because opioid receptors are more densely distributed at the level of C fibers transmission, the most effective function of opioid action is in reducing dull, poorly localized pain signals.

Descending Pain Pathways:

Mu and delta opioid agonists activate a system descending pain modulatory interneurons - Excitation of the PAG activates a signalling pathway to the raphe nuclei (a serotonergic structure). This in turn activates a pathway of inhibitory interneurons which terminate at the spinal level (substantia gelatinosa) to inhibit ascending pain stimuli. Serotonergic drugs such as SSRIs or TCAs are often used as an adjunct to opioid analgesia - these drugs are believed to activate the descending modulatory system, and thus potentiate the action of opioid analgesics.

The descending modulatory system plays a role in both inhibiting pain; communicating to the spinal cord how much pain transduction is necessary before becoming excessive, and also in facilitating pain, by potentiating transduction of ascending signals. In neuropathic pain states, the modulatory system may continue facilitating ascending pain flow long past the natural course of the injury or illness, leading to a perpetual state of chronic pain in the absence of any injury or damage.

Limbic Area ("Pleasure Center"):

Meanwhile in the mesocorticolimbic structures of the forebrain, mu receptor activation inhibits the release of GABA, a major inhibitory neurotransmitter, in the ventral tegmental area (VTA), leading to a subsequent firing of dopamine from the VTA into the nucleus accumbens - This maniests as an increase in mood, a blunted emotional perception of pain, as well as the reinforcement and reward often associated with opioid use and misuse.

Hypothalamus and Hypothalamic Pituitary Adrenal Axis:

Action on various opioid receptor sites in the hypothalamus and pituitary gland affects a range of autonomic functions. Pupil constriction (miosis), reduced perspiration and mucosal secretions, dry eyes and mouth, reduced libido, lowered body temperature, reduced sensitivity to cold. Opioid activity in the hypothalamus inhibits adverse, and sometimes dangerous, physiological or homeostatic responses to pain.


Activation of mu receptors in the locus coeruleus (LC) inhibits noradrenergic activity and reduces the activity of the sympathetic nervous system. Binding of an opioid agonist in this area leads to anxiolysis, relaxation, sedation, and possibly an affect on libido. Activation of mu receptors in the medulla inhibits certain vital functions such as brain-O2 responsiveness, resulting in slowed breathing & reduced blood-oxygenation. Opioid receptor activity in the medulla, specifically the chemoreceptor trigger zone, often induces nausea and vomiting.

Opioids & Acetylcholine Receptors:

Acetylcholine is an excitatory neurotransmitter occurring centrally and peripherally - it plays a role in mediating numerous involuntary functions of the autonomic nervous system, including cardiac-functions, urinary function, intestinal propulsion, gastric secretions and salivation. Acetylcholine is the primary ligand for the acetylcholine receptor. Acetylcholine receptors facilitate such functions by mediating muscle contractions in these tissues. This is indeed why many anticholinergic drugs act as neuromuscular blockers and skeletal muscle relaxants.

Though acetylcholine is the primary neurotransmitter of cholinergic receptors, these receptors respond to similar compounds as well - in the same way that the 'endorphin' receptors respond to opioid drugs. There are two major types of acetylchoiline receptor; these have been classified the muscarinic ACh-receptor and the nicotinic ACh-receptor. These too are further divided into their various receptor subtypes. To state the obvious; the nicotinic ACh-receptor is agonized (i.e. activated) by nicotine, while the muscarinic ACh-receptor is agonized by muscarine.

A drug may also however bind to a cholinergic receptor but not produce an agonist response, thus serving simply to block the receptor. Such a compound is considered an acetylcholine antagonist, or an anticholinergic. There are three types of anticholinergic agents: ganglionic blockers, antimuscarinic agents and antinicotinic agents.

Related Reading: Overview of opioid receptor types and their function 

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