Other GPCRs

The NK1 receptor and its endogenous peptide agonist, substance P (SP), have been studied as potential targets for the treatment of pain for many years. Although strong evidence from animal models demonstrated analgesic properties of the available selective NK1 antagonists, they have not proven effective in humans. SP is found in small unmyelinated sensory fibers associated with nociception.165 NK1 receptors are expressed in the dorsal horn of the spinal cord where SP is released following nociceptive stimuli, and NK1 receptor expression is modulated during specific pain states in animal models.166

Although NK1 antagonists did not consistently demonstrate analgesia in acute models of pain, a number of positive results involving neuronal injury and induction of inflammation were reported in animal models. The lack of success of a number of clinical trials in demonstrating analgesic effects in humans (except for some efficacy in dental pain)167 has been a major disappointment.168 Although the NK1-SP system in the spinal cord is very similar in humans and rodents, differences in supraspinal systems may attribute to the species differences. Alternatively, achieving sufficient receptor occupancy in vivo and selection of appropriate pain states have been suggested as issues to address in future clinical trails of NK1 antagonists.

Cannabinoid receptor subtypes CB1 and CB2 are activated by endogenous lipids such as anandamide, known collectively as endocannabinoids. Similar to the opioid system, the effects of exogenous ligands for these receptors, including the active components of marijuana (cannabis), were studied long before identification of the receptors. Although involvement of CB receptors in pain modulation has been suggested for many years, the lack of selective small molecules and the stigma of association with drugs of abuse slowed progress in this field.

It is now becoming clear that effective analgesia can be separated from psychotropic effects by selective modulation of CB receptors. Data from animal models demonstrated high efficacy analgesia in response to all types of nociception (acute and inflammatory states) tested with a number of agents currently under investigation.169170 Clinical trials using synthetic cannabinoids and extracts of whole plant cannabis (including delta-9-tetrahydocannabinol and cannabidiol) have shown mixed results for efficacy in treating pain and muscle spasticity associated with multiple sclerosis and various neuropathic pain conditions.170174 The results of future trials using more selective agents with properties that allow oral dosing are eagerly awaited.

More speculative, early stage research on the involvement of other GPCRs in pain perception is based largely on localization of receptors in nociception-related pathways. Further studies with selective pharmacological agents are needed to reveal the involvement of GPCRs such as the sensory neuron-specific receptors (SNSRs), galanin receptors, and neuromedin U (NMU) receptors in pain modulation.175

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