How do opioids produce analgesia?

In this step, Dr Rachel Coathup, Consultant in Anaesthesia and Acute Pain Medicine at UCLH, and Dr Harriet Scott, Specialty Registrar in Anaesthesia and Pain Medicine at Barts Health, discuss how opioids interact with opioid receptors and nociceptive pathways to produce analgesia.

As mentioned in Step 2.2, opioids work by binding to opioid receptors which are distributed throughout the body. They can be found in the central nervous system (CNS), but also in the cardiovascular, respiratory, gastrointestinal and immune systems, vas deferens and peripheral joints.

In the brain and brainstem, opioid receptors are found in high concentrations in the periaqueductal grey (PAG), locus coeruleus and the rostroventral medulla, all areas which are important in pain processing. In the spinal cord, opioid receptors are found in the substantia gelatinosa of the dorsal horn, another key part of the pain signalling pathways.

Locations of mu opioid receptors (MOR) in the brain – labelled locations are only approximate

Why do we have these specific opioid receptors? Are we designed to take opioid drugs?

Our bodies naturally produce substances which bind to and activate opioid receptors. These are known as endogenous opioids. There are three groups of endogenous opioids: endorphins, enkephalins and dynorphins. They produce analgesia and feelings of euphoria as well as being involved in appetite regulation and reward processing. We will discuss these in more detail in the Step 2.7.

Opioids, both endogenous and exogenous (ie opioid drugs), bind to specific opioid receptors to exert their effects. There are four different opioid receptor subtypes, which have been variably named by different classification systems over the years:

• (mu) (mu) opioid receptor (MOP) – named after morphine
• (delta) (delta) opioid receptor (DOP) – named after vas deferens where it was first found
• (kappa) (kappa) opioid receptor (KOP) – named after ketocyclazocine, the first ligand found to act at this receptor
• Nociceptin/Orphanin FQ (NOP) – named as the nociception receptor

The opioid receptors subtypes have similar structures but produce different clinical effects. These are summarised in the table below. We will focus on the (mu) (mu) opioid receptor (MOP), as most clinically relevant opioids have their primary activity at this receptor and are therefore known as mu-agonists.

Opioid receptor subtypes and their clinical effects

When someone takes an opioid, how does it produce pain relief?

First, the drug must move from the bloodstream to enter the CNS where it will bind to opioid receptors in the brain and spinal cord. As we mentioned, mu receptors are present at high concentrations in many key areas of the nociceptive pathways (the pathways involved in the transmission of pain).

Before we explore in more detail how the opioid receptors work, let’s refresh our knowledge of how pain signals are transmitted.

Signals travel along neurons as flows of positive charge, known as action potentials. These signals travel from one neuron to another via the release of various neurotransmitters at the connection between the two (the synapse or synaptic cleft).

These neurotransmitters can be excitatory or inhibitory. Neurons have voltage-gated ion channels on their surface, which essentially means they only open to let ions through when there is increased positive charge. When the action potential reaches the end of the first neuron (the presynaptic neuron), voltage-gated calcium channels open and allow calcium to flow in. The increased levels of calcium trigger neurotransmitters to be released in the synaptic cleft.

If the neurotransmitter released is excitatory, such as glutamate, then when it binds to the receptors on the surface of the neighbouring neuron (the postsynaptic membrane) it activates sodium channels in this neuron allowing positively charged sodium ions to flow in. This increase in positive charge within the postsynaptic neuron is known as depolarisation. The depolarisation propagates further action potentials, effectively conducting the signal along the nerve.

Alternatively, if the neurotransmitter released is inhibitory (such as GABA), then when it binds to the postsynaptic receptors it causes chloride channels to open in the second neuron. As chloride is a negatively charged ion, the inside of the neuron will become more negatively charged. The negative charge stops the sodium channels from opening, and an action potential does not form. The signal is therefore not conducted. This process is known as hyperpolarisation.

How do opioids affect neuronal transmission?

The overall effect of an opioid agonist binding to the opioid receptor depends on the receptor’s location:

1. Presynaptic receptors – opioids inhibit the presynaptic neuron from releasing neurotransmitter.
2. Postsynaptic receptors – opioids inhibit the postsynaptic neuron from depolarising (decreased neuron excitability).

In either case, the effect is that the opioid will tend to stop a signal from being transmitted from one neuron to another along the nerve, preventing pain signals from being conducted.

How do opioid receptors produce these effects?

Opioid receptors are G protein-coupled receptors (GPCR). They are situated in the cell membrane and transmit signals from the outside of the cell to a messenger protein inside the cell, called a G protein, which then sets off a series of intracellular reactions.

When an opioid binds to its receptor, the G protein separates into two subunits. In the presynaptic neuron, one of these subunits interacts with the voltage-gated calcium channels, preventing them from opening and stopping neurotransmitters from being released into the synaptic cleft.

In the postsynaptic neuron another subunit interacts with potassium channels. This time positively-charged potassium ions flow out through the channel leading to hyperpolarisation. Therefore, even if neurotransmitter has been released from the presynaptic neuron, depolarisation cannot occur as the loss of potassium ions from inside the postsynaptic neuron opposes the effect of positive sodium ions flowing into the neuron, preventing an action potential from forming.

Activation of the G protein receptor also reduces formation of an important signalling molecule inside the cell called cyclic adenosine monophosphate (cAMP) by inhibiting an enzyme essential in its production – adenylyl cyclase. Reduced cAMP levels mean that various pathways are no longer activated.

The combined reduction in transmission of nerve impulses and inhibition of neurotransmitter release which results from these processes leads to overall reduced neuronal excitability, which prevents signals from flowing between neurons, reducing the sensation of pain.

Where in the pain pathway do opioids act?

As human beings, we have two main nociceptive (pain) pathways:

1. The ascending pathway
2. The descending pathway

The ascending pathway

Following tissue damage, primary sensory neurones send a signal to the dorsal horn in the spinal cord. Here they meet secondary neurones which transmit the signal up the spinal cord to the thalamus.

At the thalamus, secondary neurones synapse with tertiary neurones which activate areas of the sensory cortex. In the cortex the pain signals are modulated further by a person’s emotions and psychology, leading to the subjective experience of pain.

The pre- and post-synaptic inhibition caused by opioids, described in the previous section, blocks communication between the primary and secondary neurons, reducing the number and intensity of pain signals reaching the brain.

The descending pathway

A less commonly discussed pain pathway is the descending pathway, which has the effect of reducing pain transmission. Opioids enhance the activity of this pathway.

Neurons in this descending pathway are normally inactive because they are under the control of the neurotransmitter GABA, which is inhibitory. Opioids stop GABA being released, causing these neurons not to be inhibited. This leads to an increased firing of signals from areas in the midbrain (such as the PAG and the nucleus raphe magnus) which connect directly with the dorsal horn of the spinal cord.

Here, special endogenous opioid-releasing neurons, called inhibitory interneurons, are activated, preventing communication between the primary and the secondary neuron, decreasing transmission of pain signals via the ascending pathway.

Peripheral actions

In addition to acting centrally, opioid receptors are also found peripherally in areas outside of the CNS. Inflammation (caused by tissue damage, for example) leads to increased expression of these receptors. Opioids bind to opioid receptors on the primary neurons leading to reduced transmission of nociceptive signals.

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