Opioid pharmaceuticals and addiction: the issues, and research directions seeking solutions

Abstract

There are few pharmaceuticals superior to opiates for the treatment of pain. However, with concerns of addiction, withdrawal and questionable efficacy for all types of pain, these compounds are far from a magical panacea for pain-relief. As it is unlikely that other classes of compounds will supersede the opioids in the very near future, it is important to both optimize current opioid therapies and curb the astounding diversion of opioids from their intended analgesic use to non-medical abuse. In optimizing opioid therapeutics it is necessary to enhance the clinical awareness of the benefits of treating pain and combine this with aggressive strategies to reduce diversion for non-medical use. At the heart of the issue of opioid misuse is the role of opioid systems in the reward circuitry, and the adaptive processes associated with repetitive opioid use that manifest during withdrawal. Emerging pharmacological insights of opioid receptors will be reviewed that provide future hope for developing opioid-based analgesics with reduced addictive properties and perhaps, reduced opponent processes. In addition, with the increased understanding of nociceptive circuitry and the molecules involved in transmitting pain, new therapeutic targets have become evident that may result in effective analgesics either alone or in combination with current opioid therapies.

Fig. 1

Indicators of increased opioid use between 1997 and 2006. (a) Prescription and sales of opioid drugs from 1997 to 2006. Data from the Drug Enforcement Administration (DEA, 2007) show an increase in prescription number as well as a dramatic increase in the amount of opiate prescribed between 1997 and 2006. (b) Past Year Initiates. Results from Substance Abuse and Mental Health Services Administration (SAMHSA) of the 2006 National Survey on Drug Use and Health indicates past year initiation of non-medical opioid pain reliever use has been significantly higher than that of marijuana (SAMHSA, 2008).

Fig. 2

Mu receptor signaling complexes. (A) Mu receptor signaling complexes. Agonists of the mu receptor bind to extracellular regions of this GPCR. This leads to dissociation of the cognate G-proteins from the receptor which, either through a conformational change, or physical dissociation, separate into the αi and βγ subunits. G-protein uncoupling is often followed by receptor phosphorylation, typically mediated by the GPCR kinases, GRK2 and GRK3, and potentially other kinases such as the Calcium/CaMK11 or Protein Kinase A or C. Receptor phosphorylation initiates desensitization of the receptor and leads to the recruitment of the scaffolding protein β-arrestin 2 and perhaps other non-G-protein mediated components such as by c-Src. The α or βγ subunits of the G-proteins initiate a series of signaling cascades or second messenger systems. The Gαi subunit couples with the adenylate cyclase cascade to inhibit intracellular accumulation of cAMP. The Gβγ subunits couple with ion channels such as the inwardly rectified K⁺ channels and the Ca²⁺ channels to inhibit neuronal activity and may also modulate adenylate cyclase. In addition to these pathways, mu receptor agonists activate the MAP kinase cascade in a G-protein/β-arrestin/GRK3 dependent manner, and so affect multiple processes ranging from nuclear events orchestrated by the MAP kinase cascade and membrane-localized events such as receptor desensitization and transactivation of the receptor tyrosine kinase, Epidermal Growth Factor (EGF) receptor to influence the EGF pathway. (B) Mu receptor trafficking complexes. Following mu receptor activation by ligands such as DAMGO, etorphine, fentanyl and methadone, the mu receptor internalizes in DRG neurons. As the mu receptor is a Class A receptor, it rapidly dissociates from β-arrestin 2 and is internalized into clathrin-coated pits. These pits evolve into Rab5 associated early endosomes and the receptor then recycles back to the cell membrane through either the Rab4- or Rab11-mediated early or late recycling pathways. The recycled receptor is dephosphorylated, resensitized and capable of signaling when returned to the cell membrane. Mu receptor internalization and desensitization requires an intact 3-dimensional structure, as suggested from cells lacking the actin-cytoskeleton protein, Filamin A (Onoprishvili et al., 2008). Such ligand-dependent recycling of the mu receptor is dependent on the sequence of the C-terminus. If this sequence is exchanged with that of the delta opioid receptor, β-arrestin recruitment is prolonged and the receptor is degraded rather than recycled (Walwyn et al., 2006). The internalization of the mu receptor is p38 dependent, this kinase phosphorylates the early endosomal antigen 1 and Rabenosyn5, both components of the early endosome (Mace et al., 2005). Interestingly the non-internalizing mu receptor agonist, morphine, neither activates p38 nor internalizes the mu receptor suggesting that p38 activation is a critical component of mu receptor internalization (Tan et al., 2009). Although we do not know whether ligand-dependent internalization of the mu receptor requires the non-receptor tyrosine kinase, c-Src, we have found that c-Src and β-arrestin 2 are required for ligand-independent or constitutive receptor internalization and recycling. This pathway removes constitutively, or tonically, active mu receptors from the cell membrane in a c-Src and β-arrestin 2 manner. However, if either of these 2 molecules are inhibited the receptor remains on the cell membrane with measurable physiological effects.

Fig. 3

Morphine vs DAMGO receptor signaling complexes. The differential internalization, pharmacology of desensitization and signaling of the DAMGO-treated receptor (A) and morphine-treated mu receptor (B) in DRG neurons (see text) can be explained by ligand-specific receptor complex formation. An interesting difference between the morphine vs DAMGO-activated mu opioid receptors is a ligand-dependent interaction with the α_2A adrenergic receptor. Our data suggest that in DRG neurons this ligand-dependent receptor-receptor interaction is p38, β-arrestin 2 and possibly internalization-dependent. DAMGO, an internalizing mu receptor agonist, results in both internalization and desensitization of the α_2A receptor whereas morphine, a non-internalizing mu receptor agonist, neither internalizes nor desensitizes the α_2A receptor (Tan et al., 2009).